US20230213525A1 - Detecting microbial infection in wounds - Google Patents

Detecting microbial infection in wounds Download PDF

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Publication number
US20230213525A1
US20230213525A1 US16/090,091 US201716090091A US2023213525A1 US 20230213525 A1 US20230213525 A1 US 20230213525A1 US 201716090091 A US201716090091 A US 201716090091A US 2023213525 A1 US2023213525 A1 US 2023213525A1
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Prior art keywords
reactive
wound
cbm
chitosan
anchor
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Inventor
Michael Burnet
Andrea HEINZLE
Eva Sigl
Daniel Luschnig
Clemens GAMERITH
Gregor TEGL
Georg GUEBITZ
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Universitaet fuer Bodenkultur Wien BOKU
ACIB GmbH
Qualizyme Diagnostics GmbH and Co KG
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Universitaet fuer Bodenkultur Wien BOKU
ACIB GmbH
Qualizyme Diagnostics GmbH and Co KG
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Priority to US16/090,091 priority Critical patent/US20230213525A1/en
Publication of US20230213525A1 publication Critical patent/US20230213525A1/en
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/52—Use of compounds or compositions for colorimetric, spectrophotometric or fluorometric investigation, e.g. use of reagent paper and including single- and multilayer analytical elements
    • G01N33/528—Atypical element structures, e.g. gloves, rods, tampons, toilet paper
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    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
    • G01N33/583—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances with non-fluorescent dye label
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    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/544—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being organic
    • G01N33/548—Carbohydrates, e.g. dextran
    • G—PHYSICS
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    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
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    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
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    • G01N33/573—Immunoassay; Biospecific binding assay; Materials therefor for enzymes or isoenzymes
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    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
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    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
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    • G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
    • G01N33/582—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances with fluorescent label
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    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • C07K14/24—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Enterobacteriaceae (F), e.g. Citrobacter, Serratia, Proteus, Providencia, Morganella, Yersinia
    • C07K14/245—Escherichia (G)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/20—Fusion polypeptide containing a tag with affinity for a non-protein ligand
    • C07K2319/21—Fusion polypeptide containing a tag with affinity for a non-protein ligand containing a His-tag
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
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    • G01N2333/902—Oxidoreductases (1.)
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    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/902—Oxidoreductases (1.)
    • G01N2333/908—Oxidoreductases (1.) acting on hydrogen peroxide as acceptor (1.11)
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    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
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    • G01N2333/914—Hydrolases (3)
    • G01N2333/916—Hydrolases (3) acting on ester bonds (3.1), e.g. phosphatases (3.1.3), phospholipases C or phospholipases D (3.1.4)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/914—Hydrolases (3)
    • G01N2333/924—Hydrolases (3) acting on glycosyl compounds (3.2)
    • G01N2333/936—Hydrolases (3) acting on glycosyl compounds (3.2) acting on beta-1, 4 bonds between N-acetylmuramic acid and 2-acetyl-amino 2-deoxy-D-glucose, e.g. lysozyme
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/914—Hydrolases (3)
    • G01N2333/948—Hydrolases (3) acting on peptide bonds (3.4)
    • G01N2333/95—Proteinases, i.e. endopeptidases (3.4.21-3.4.99)
    • G—PHYSICS
    • G01—MEASURING; TESTING
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    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/914—Hydrolases (3)
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    • G01N2333/966—Elastase
    • G—PHYSICS
    • G01—MEASURING; TESTING
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    • G01N2400/00—Assays, e.g. immunoassays or enzyme assays, involving carbohydrates
    • G01N2400/10—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • G01N2400/38—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence, e.g. gluco- or galactomannans, e.g. Konjac gum, Locust bean gum, Guar gum
    • G01N2400/40—Glycosaminoglycans, i.e. GAG or mucopolysaccharides, e.g. chondroitin sulfate, dermatan sulfate, hyaluronic acid, heparin, heparan sulfate, and related sulfated polysaccharides
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/26—Infectious diseases, e.g. generalised sepsis

Definitions

  • the Sequence Listing associated with this application includes the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825.
  • the Sequence Listing is hereby incorporated by reference in its entirety.
  • the Sequence Listing includes no new matter.
  • the name of the ASCII text file which includes the Sequence Listing is Sequence_Listing_CVT05_40137 - Sequence Listing.
  • the date of creation is Oct. 29, 2020.
  • the size of the file is 3 KB.
  • Embodiments described herein generally relate to wound healing, and in particular to compositions and methods for the detection and treatment of wounds.
  • Wound healing is a complex dynamic process that results in the restoration of anatomic continuity and function: an ideally healed wound is one that has returned to normal anatomic structure, function, and appearance.
  • the inflammatory phase is particularly important to the wound healing process, wherein biochemical reactions at the wound situs facilitate healing but also cause tissue breakdown due to production of excess proteases.
  • pathogens in a wound can produce toxins (e.g., Clostridium species), generate noxious metabolites like ammonia that raise pH (e.g., Proteus species), activate or produce tissue lytic enzymes like proteases, or promote tissue invasion, thereby leading to an increase in the size or seriousness of the wound. In a worst case, pathogens can leave the wound and cause sepsis.
  • toxins e.g., Clostridium species
  • generate noxious metabolites like ammonia that raise pH e.g., Proteus species
  • activate or produce tissue lytic enzymes like proteases
  • promote tissue invasion thereby leading to an increase in the size or seriousness of the wound.
  • pathogens can leave the wound and cause sepsis.
  • a variety of assessment techniques and/or tools are employed in the clinical and veterinary setting.
  • Current methods of assessing an infected wound are based primarily on assaying for a variety of parameters associated with the wound. For instance, a wound may be assessed visually, length and depth measurements may be taken, digital photography may be used where available to track the visual condition and size of a wound (Krasner et al., supra).
  • diagnosis of infection is based on measurement of secondary parameters, such as, odor, presence of local pain, heat, swelling, discharge, and redness Many of these clinical indicators, such as inflammation and discharge have a low predictive value of infection in wounds.
  • the number(s) and type(s) of pathogenic flora at the wound situs may be determined using laboratory and/or clinical diagnostic procedures. Swabbing of a wound followed by microbiology testing in the hospital laboratory is an option for confirmation of bacterial colonization and identification of the strains associated with infection, thus allowing for the prescription of correct antibiotic course.
  • this process is time consuming and labor intensive. Delay in diagnosis of infection can delay the administration of antibiotics and may increase the risk of developing sepsis.
  • the technology disclosed herein provides for compositions and methods of detecting infected and/or chronic wounds.
  • the disclosed technology improves upon exiting assays by: increasing the sensitivity, precision and specificity of detection of infected wounds; providing for the ability of qualitative and quantitative measurements; and, increasing the speed of detection of infected wounds in situ and in real-time.
  • the assays and methods described herein are partly based on the use of specific reagents that detect biomarkers and/or probes which are present in infected or chronic wounds.
  • the detection process may involve use of reagents that are specific to the markers present in infected wounds but not non-infected or non-chronic wounds and the detection step may involve qualitative or quantitative measurements of the signal(s) that are generated when the probe is acted upon by the marker.
  • the probes comprise modified enzyme substrates that are specific to the enzyme, which generate signals that may be optionally amplified. This greatly improves efficiency and specificity of detection.
  • a plurality of detection probes, each specific for one or more targets, e.g., enzymes that are specific to the wounds, may be employed.
  • the experimental results disclosed herein confirm that the novel probes and the assay techniques based thereon are capable of detecting and characterizing various types of wounds.
  • the reagents of the disclosed technology may be used together with therapeutic molecules such as antibiotics, antifungal agents, etc. to monitor and evaluate treatment and management of chronic wounds.
  • Embodiments described herein are based, in part, on the discovery that cells of the immune system, including enzymes generated thereby, may serve as markers in the early diagnosis of wounds. These cells, e.g., neutrophils, are recruited at the wound situs to combat infection, do so by engulfing bacteria (and other pathogens) and/or neutralizing them with enzymes.
  • Some enzymes are specific towards proteins (e.g., elastase, cathepsin G), others are specific towards cell wall components (e.g., lysozyme) and yet others mediate protein denaturation (e.g., NADPH oxidase, xanthine oxidase, myeloperoxidase (MPO) and other peroxidases).
  • proteins e.g., elastase, cathepsin G
  • cell wall components e.g., lysozyme
  • mediate protein denaturation e.g., NADPH oxidase, xanthine oxidase, myeloperoxidase (MPO) and other peroxidases.
  • MPO myeloperoxidase
  • neutrophils are generally only short-lived and when they lyse in the area of the infection, they release the contents of their lysosomes including the enzymes, which can then be
  • various embodiments described herein utilize the detection of enzyme markers, which are indicative of the presence of myeloid cells, and neutrophils in particular, in a biological sample of interest, for example, wound tissue. Increased level or activity of such enzymes in the wound fluid, therefore, corresponds to a heightened bacterial challenge and a manifestation of disturbed host/bacteria equilibrium in favor of the invasive bacteria.
  • a chemical entity comprising a compound with the structure A-I (Formula I) wherein, A is an anchor; and I is an indicator region.
  • a chemical entity comprising a compound with the structure A-I (Formula I), wherein the anchor A is covalently associated with the indicator I via a covalent interaction to form a recognition site S.
  • a chemical entity comprising a compound with the structure A-I (Formula I), wherein the anchor A is covalently associated with the indicator I via a covalent interaction to form a recognition site S, and wherein the recognition site (S) is specific for a wound-specific hydrolase.
  • the hydrolase is a glycosidase or a protease.
  • the protease is elastase, cathepsin G or myeloperoxidase.
  • a chemical entity comprising a compound with the structure A-I (Formula I) wherein, A is an anchor; and I is an indicator region, wherein the anchor A comprises a polysaccharide, a cellulose, a polyacrylate, a polyethyleneimine, a polyacrylamide, a peptidoglycan, or a chitosan, or a monomer thereof, an oligomer thereof, a derivative thereof, a mixture or a combination thereof.
  • a chemical entity comprising a compound with the structure A-I (Formula I) wherein, A is an anchor; and I is an indicator region, wherein the anchor A comprises chitosan or a monomer thereof, an oligomer thereof, a derivative thereof, a mixture or a combination thereof.
  • a chemical entity comprising a compound with the structure A-I (Formula I) wherein, A is an anchor; and I is an indicator region, wherein the anchor A comprises a monomer of chitosan comprising D-glucosamine or N-acetyl-D-glucosamine, an oligomer thereof, or a combination thereof.
  • a chemical entity comprising a compound with the structure A-I (Formula I) wherein, A is an anchor; and I is an indicator region, wherein the anchor A comprises at least two units of D-glucosamine, N-acetyl -D-glucosamine or a combination thereof.
  • a chemical entity comprising a compound with the structure A-I (Formula I) wherein, A is an anchor; and I is an indicator region, wherein the anchor A comprises a randomly substituted partial N-, partial O-acetylated chitosan, chitosan oligosaccharide, carboxymethyl chitosan, or hydroxyalkyl chitosan or a derivative thereof.
  • a chemical entity comprising a compound with the structure A-I (Formula I) wherein, A is an anchor; and I is an indicator region, wherein the anchor A comprises a randomly substituted partial N-, partial O-acetylated chitosan.
  • a chemical entity comprising a compound with the structure A-I (Formula I) wherein, A is an anchor; and I is an indicator region, wherein the anchor A comprises a randomly substituted partial N-, partial O-acetylated chitosan, wherein the acetylated chitosan comprises a degree of acetylation (DA) between about 40% to about 90%.
  • A is an anchor
  • I is an indicator region
  • the anchor A comprises a randomly substituted partial N-, partial O-acetylated chitosan
  • the acetylated chitosan comprises a degree of acetylation (DA) between about 40% to about 90%.
  • DA degree of acetylation
  • a chemical entity comprising a compound with the structure A-I (Formula I) wherein, A is an anchor; and I is an indicator region, wherein the anchor A comprises a randomly substituted partial N-, partial O-acetylated chitosan, wherein the acetylated chitosan comprises a degree of acetylation (DA) of greater than 50%.
  • a chemical entity comprising a compound with the structure A-I (Formula I) wherein, A is an anchor; and I is an indicator region, wherein the anchor A comprises a randomly substituted partial N-, partial O-acetylated chitosan, wherein the chitosan is halogenated.
  • a chemical entity comprising a compound with the structure A-I (Formula I) wherein, A is an anchor; and I is an indicator region, wherein the anchor A comprises chitosan or a monomer thereof, an oligomer thereof, a derivative thereof, a mixture or a combination thereof.
  • a chemical entity comprising a compound with the structure A-I (Formula I) wherein, A is an anchor and I is an indicator region, wherein the indicator (I) or a motif therein is conjugated to the anchor and the conjugate is a substrate for a glycosidase.
  • a chemical entity comprising a compound with the structure A-I (Formula I) wherein, A is an anchor and I is an indicator region, wherein the indicator (I) or a motif therein is conjugated to the anchor and the conjugate is a substrate for a glycosidase.
  • a chemical entity comprising a compound with the structure A-I (Formula I) wherein, A is an anchor and I is an indicator region, wherein the indicator (I) or a motif therein is conjugated to the anchor and the conjugate is a substrate for lysozyme.
  • a chemical entity comprising a compound with the structure A-I (Formula I) wherein, A is an anchor and I is an indicator region, wherein the indicator (I) or a motif therein is conjugated to the anchor via a glycosidic bond at the la- carbon of chitosan or a monomer thereof, an oligomer thereof, or a derivative thereof.
  • a chemical entity comprising a compound with the structure A-I (Formula I) wherein, A is an anchor and I is an indicator region, wherein the indicator (I) further comprises a dye containing a sulfonylethyl-hydrogensulphate-reactive-group or a dye containing a dichlortriazine reactive-group.
  • a chemical entity comprising a compound with the structure A-I (Formula I) wherein, A is an anchor and I is an indicator region, wherein the indicator (I) further comprises a dye which is reactive black 5, remazol brilliant blue, reactive violet 5 or reactive orange 16 or a combination thereof.
  • a chemical entity comprising a compound with the structure A-I (Formula I) wherein, A is an anchor and I is an indicator region, wherein the indicator (I) further comprises a dye which is reactive blue 4, reactive red 120, reactive blue 2, reactive green 19, or reactive brown 10, or a combination thereof.
  • a chemical entity comprising a compound with the structure A-I (Formula I) wherein, A is an anchor and I is an indicator region, wherein the indicator (I) comprises a detectable label selected from the group consisting of a luminescent molecule, a chemiluminescent molecule, a fluorochrome, a fluorescent quenching agent, a lipid, a colored molecule, a radioisotope, a scintillant, biotin, avidin, streptavidin, protein A, protein G, an antibody or a fragment thereof, a polyhistidine, Ni2+, a Flag tag, a myc tag, a heavy metal, and an enzyme.
  • A is an anchor and I is an indicator region
  • the indicator (I) comprises a detectable label selected from the group consisting of a luminescent molecule, a chemiluminescent molecule, a fluorochrome, a fluorescent quenching agent, a lipid, a colored molecule, a radiois
  • a chemical entity comprising a compound with the structure A-I (Formula I) wherein, A is an anchor and I is an indicator region and the anchor is directly conjugated to the indicator via a glycosidic linkage.
  • a chemical entity comprising a compound with the structure A-I (Formula I) wherein, A is an anchor and I is an indicator region and the anchor is directly conjugated to the indicator via a glycosidic linkage, wherein the indicator is selected from the group consisting of reactive black 5, remazol brilliant blue, reactive violet 5 or reactive orange 16, reactive blue 4, reactive red 120, reactive blue 2, reactive green 19 and reactive brown 10, or a combination thereof.
  • a chemical entity comprising a compound with the structure A-I (Formula I) wherein, A is an anchor and I is an indicator region, wherein the indicator comprises a hydrophilic binding module (CBM) from Cellobiohydrolase I (Trichoderma reesei) or the hydrophobic binding module (PDB) from Polyhydroxyalkanoate depolymerase ⁇ Alcaligenes faecalis) or a chimeric variant thereof.
  • CBM hydrophilic binding module
  • PDB hydrophobic binding module
  • a chemical entity comprising a compound with the structure A-I (Formula I) wherein, A is an anchor and I is an indicator region, wherein the indicator comprises a hydrophilic binding module (CBM) from Cellobiohydrolase I ⁇ Trichoderma reesei) or the hydrophobic binding module (PDB) from Polyhydroxyalkanoate depolymerase ⁇ Alcaligenes faecalis) or a chimeric variant thereof, wherein the anchor comprises cellulose or a derivative thereof or polyethylene terephthalate or a derivative thereof.
  • CBM hydrophilic binding module
  • PDB hydrophobic binding module
  • the anchor comprises cellulose or a derivative thereof or polyethylene terephthalate or a derivative thereof.
  • a chemical entity comprising a compound with the structure A-I (Formula I) wherein, A is an anchor and I is an indicator region, wherein the indicator comprises a hydrophilic binding module (CBM) from Cellobiohydrolase I ⁇ Trichoderma reesei) or the hydrophobic binding module (PDB) from Polyhydroxyalkanoate depolymerase ⁇ Alcaligenes faecalis) or a chimeric variant thereof, wherein the anchor comprises cellulose or a derivative thereof or polyethylene terephthalate or a derivative thereof.
  • CBM hydrophilic binding module
  • PDB hydrophobic binding module
  • the anchor comprises cellulose or a derivative thereof or polyethylene terephthalate or a derivative thereof.
  • a chemical entity comprising a compound with the structure A-I (Formula I) wherein, A is an anchor and I is an indicator region, wherein the indicator comprises a hydrophilic binding module (CBM) from Cellobiohydrolase I ⁇ Trichoderma reesei) or a chimeric variant thereof and the anchor comprises cellulose or a derivative thereof, wherein the indicator is hydrophilically associated with the anchor.
  • A is an anchor and I is an indicator region
  • the indicator comprises a hydrophilic binding module (CBM) from Cellobiohydrolase I ⁇ Trichoderma reesei) or a chimeric variant thereof and the anchor comprises cellulose or a derivative thereof, wherein the indicator is hydrophilically associated with the anchor.
  • CBM hydrophilic binding module
  • a chemical entity comprising a compound with the structure A-I (Formula I) wherein, A is an anchor and I is an indicator region, wherein the indicator comprises Polyhydroxyalkanoate depolymerase ⁇ Alcaligenes faecalis) and the anchor comprises polyethylene terephthalate or a derivative thereof, wherein the indicator is hydrophobically associated with the anchor.
  • a chimeric construct comprising polynucleotide sequences encoding a trxA (thioredoxin) or a portion thereof, a spacer sequence encoding a histidine-tag and an enterokinase cleavage site, or a portion thereof.
  • a chimeric construct comprising polynucleotide sequences encoding a trxA (thioredoxin) gene, a spacer sequence encoding a histidine-tag and an enterokinase cleavage site, or a portion thereof.
  • trxA thioredoxin
  • a chimeric construct comprising polynucleotide sequences encoding a trxA (thioredoxin) or a portion thereof, a spacer sequence encoding a poly-histidine-tag and an enterokinase cleavage site, or a portion thereof.
  • the spacer sequence encodes a hexahistidine (His6) tag [SEQ ID NO: 11.
  • a chimeric construct comprising polynucleotide sequences encoding a trxA (thioredoxin) or a portion thereof, a spacer sequence encoding a poly-histidine-tag and an enterokinase cleavage site, or a portion thereof and an enterokinase cleavage site (Asp Asp Asp Lys) [SEQ ID NO: 21.
  • a chimeric construct comprising polynucleotide sequences encoding a trxA (thioredoxin) or a portion thereof, a spacer sequence encoding a poly-histidine-tag and an enterokinase cleavage site, or a portion thereof and an enterokinase cleavage site (Asp Asp Asp Lys) [SEQ ID NO: 21 and an elasubl sequence.
  • the elasubl sequence is located subsequent to the enterokinase cleavage site.
  • the elasubl sequence encodes for functional amino acids selected from the group consisting of cysteine, lysine, arginine, glutamine, asparagine, glutamic acid, aspartic acid, serine, threonine or tyrosine.
  • a chimeric construct comprising polynucleotide sequences encoding a trxA (thioredoxin) or a portion thereof, a spacer sequence encoding a poly-histidine-tag and an enterokinase cleavage site, or a portion thereof and an enterokinase cleavage site (Asp Asp Asp Lys) [SEQ ID NO: 21 and an elasubl sequence and a hydrophilic binding module (CBM) directly downstream to the elasubl sequence.
  • trxA thioredoxin
  • spacer sequence encoding a poly-histidine-tag and an enterokinase cleavage site, or a portion thereof and an enterokinase cleavage site
  • CBM hydrophilic binding module
  • a chimeric construct comprising polynucleotide sequences encoding a trxA (thioredoxin) or a portion thereof, a spacer sequence encoding a poly-histidine-tag and an enterokinase cleavage site, or a portion thereof and an enterokinase cleavage site (Asp Asp Asp Lys) [SEQ ID NO: 21 and an elasubl sequence and a Alcaligenes faecalis Polyhydroxyalkanoate depolymerase (PDM) sequence directly downstream to the elasubl sequence.
  • PDM Polyhydroxyalkanoate depolymerase
  • a chimeric construct comprising polynucleotide sequences encoding a trxA (thioredoxin) or a portion thereof, a spacer sequence encoding a poly-histidine-tag and an enterokinase cleavage site, or a portion thereof and an enterokinase cleavage site (Asp Asp Asp Lys) [SEQ ID NO: 21 and an elasubl sequence and a hydrophilic binding module (CBM) directly downstream to the elasubl sequence, wherein the elasubl sequence comprises nucleic acids encoding an HLE recognition site (Ala- Ala-Pro- Val) [SEQ ID NO: 31 or CatG recognition site (Ala-Ala-Pro-Phe) [SEQ ID NO: 41 or both HLE and CatG recognition sites.
  • HLE recognition site Ala-Pro- Val
  • CatG recognition site Al-Ala-Pro-Phe
  • a chimeric construct comprising polynucleotide sequences encoding a trxA (thioredoxin) or a portion thereof, a spacer sequence encoding a poly-histidine-tag and an enterokinase cleavage site, or a portion thereof and an enterokinase cleavage site (Asp Asp Asp Lys) [SEQ ID NO: 21 and an elasubl sequence and & Alcaligenes faecalis Polyhydroxyalkanoate depolymerase (PDM) sequence directly downstream to the elasubl sequence, wherein the elasubl sequence comprises nucleic acids encoding an HLE recognition site (Ala-Ala-Pro- Val) [SEQ ID NO: 31 or CatG recognition site (Ala-Ala-Pro-Phe) [SEQ ID NO: 41 or both HLE and CatG recognition sites.
  • HLE recognition site Al-Ala-Pro- Val
  • CatG recognition site Al-Ala
  • a vector comprising an expression control sequence and a chimeric construct comprising polynucleotide sequences encoding a trxA (thioredoxin) or a portion thereof, a spacer sequence encoding a poly-histidine-tag and an enterokinase cleavage site, or a portion thereof and an enterokinase cleavage site (Asp Asp Asp Lys) [SEQ ID NO: 21 and an elasubl sequence and a hydrophilic binding module (CBM) directly downstream to the elasubl sequence, wherein the elasubl sequence comprises nucleic acids encoding an HLE recognition site (Ala-Ala-Pro- Val) [SEQ ID NO: 31 or CatG recognition site (Ala-Ala-Pro-Phe) [SEQ ID NO: 41 or both HLE and CatG recognition sites.
  • a vector comprising an expression control sequence and a chimeric construct comprising polynucleotide sequences encoding a trxA (thioredoxin) or a portion thereof, a spacer sequence encoding a poly-histidine-tag and an enterokinase cleavage site, or a portion thereof and an enterokinase cleavage site (Asp Asp Asp Lys) [SEQ ID NO: 21 and an elasubl sequence and & Alcaligenes faecalis Polyhydroxyalkanoate depolymerase (PDM) sequence directly downstream to the elasubl sequence, wherein the elasubl sequence comprises nucleic acids encoding an HLE recognition site (Ala-Ala-Pro-Val) [SEQ ID NO: 31 or CatG recognition site (Ala-Ala-Pro-Phe) [SEQ ID NO: 31 or both HLE and CatG recognition sites.
  • PDM Polyhydroxyalkanoate depolyme
  • a host cell comprising a vector comprising an expression control sequence and a chimeric construct comprising polynucleotide sequences encoding a trxA (thioredoxin) or a portion thereof, a spacer sequence encoding a poly-histidine-tag and an enterokinase cleavage site, or a portion thereof and an enterokinase cleavage site (Asp Asp Asp Lys) [SEQ ID NO: 21 and an elasubl sequence and a hydrophilic binding module (CBM) directly downstream to the elasubl sequence, wherein the elasubl sequence comprises nucleic acids encoding an HLE recognition site (Ala-Ala-Pro-Val) [SEQ ID NO: 31 or CatG recognition site (Ala-Ala-Pro-Phe) [SEQ ID NO: 41 or both HLE and CatG recognition sites.
  • the host cell is a bacterial cell or an insect cell
  • a host cell comprising a vector comprising an expression control sequence and a chimeric construct comprising polynucleotide sequences encoding a trxA (thioredoxin) or a portion thereof, a spacer sequence encoding a poly-histidine-tag and an enterokinase cleavage site, or a portion thereof and an enterokinase cleavage site (Asp Asp Asp Lys) [SEQ ID NO: 21 and an elasubl sequence and a Alcaligenes faecalis Polyhydroxyalkanoate depolymerase (PDM) sequence directly downstream to the elasubl sequence, wherein the elasubl sequence comprises nucleic acids encoding an HLE recognition site (Ala-Ala-Pro-Val) [SEQ ID NO: 31 or CatG recognition site (Ala-Ala-Pro-Phe) [SEQ ID NO: 41 or both HLE and CatG recognition sites.
  • a vector comprising an
  • a method of making the protein encoded by a chimeric construct comprising polynucleotide sequences encoding (a) a trxA (thioredoxin) or a portion thereof; (b) a spacer sequence encoding a histidine-tag; (c) an enterokinase cleavage site or a portion thereof; (d) an elasubl sequence subsequent to the enterokinase cleavage site; (e) a hydrophilic binding module (CBM) directly downstream to the elasubl sequence; and (f) an HLE recognition site (Ala-Ala-Pro-Val) [SEQ ID NO: 31 or CatG recognition site (Ala-Ala-Pro-Phe) [SEQ ID NO: 41 or both HLE and CatG recognition sites in the elasubl sequence; comprising culturing a host cell comprising the chimeric construct under conditions sufficient to induce expression of the chimeric construct and obtaining the chi
  • a method of making the protein encoded by a chimeric construct comprising polynucleotide sequences encoding (a) a trxA (thioredoxin) or a portion thereof; (b) a spacer sequence encoding a histidine-tag; (c) an enterokinase cleavage site or a portion thereof; (d) an elasubl sequence subsequent to the enterokinase cleavage site; (e) a hydrophobic Alcaligenes faecalis Polyhydroxyalkanoate depolymerase (PDM) sequence directly downstream to the elasubl sequence; and (f) an HLE recognition site (Ala-Ala-Pro-Val) [SEQ ID NO: 31 or CatG recognition site (Ala-Ala-Pro-Phe) [SEQ ID NO: 41 or both HLE and CatG recognition sites in the elasub 1 sequence; comprising culturing a host cell comprising the
  • a polypeptide encoded by a chimeric construct comprising polynucleotide sequences encoding a trxA (thioredoxin) or a portion thereof, a spacer sequence encoding a poly-histidine-tag and an enterokinase cleavage site, or a portion thereof and an enterokinase cleavage site (Asp Asp Asp Lys) [SEQ ID NO: 21 and an elasubl sequence and a hydrophilic binding module (CBM) directly downstream to the elasubl sequence, wherein the elasubl sequence comprises nucleic acids encoding an HLE recognition site (Ala-Ala-Pro-Val) [SEQ ID NO: 31 or CatG recognition site (Ala-Ala-Pro-Phe) [SEQ ID NO: 31 or both HLE and CatG recognition sites.
  • composition comprising the CBM sequence containing polypeptide (“CBM polypeptide”) and a dye or a label.
  • CBM polypeptide CBM sequence containing polypeptide
  • a chemical entity comprising an anchor and an indicator region comprising the composition comprising the CBM polypeptide and the dye/label.
  • a chemical entity comprising an anchor which is cellulose or a derivative thereof and the indicator region comprising the composition comprising the CBM polypeptide and the dye/label.
  • a polypeptide encoded by a chimeric construct comprising polynucleotide sequences encoding a trxA (thioredoxin) or a portion thereof, a spacer sequence encoding a poly-histidine-tag and an enterokinase cleavage site, or a portion thereof and an enterokinase cleavage site (Asp Asp Asp Lys) [SEQ ID NO: 21 and an elasubl sequence and a Alcatigenes faecalis Polyhydroxyalkanoate depolymerase (PDM) sequence directly downstream to the elasubl sequence, wherein the elasubl sequence comprises nucleic acids encoding an HLE recognition site (Ala-Ala-Pro-Val) [SEQ ID NO: 31 or CatG recognition site (Ala-Ala-Pro-Phe) [SEQ ID NO: 41 or both HLE and CatG recognition sites.
  • a trxA thioredoxin
  • a composition comprising the PDM sequence containing polypeptide (“PDM polypeptide”) and a dye or a label.
  • PDM polypeptide PDM sequence containing polypeptide
  • a chemical entity comprising an anchor and an indicator region comprising the composition comprising the PDM polypeptide and the dye/label.
  • a chemical entity comprising an anchor which is polyethylene terephthalate or a derivative thereof and the indicator region comprising the composition comprising the PDM polypeptide and the dye/label.
  • a method for the determining the presence or absence of an enzyme selected from the group consisting of HLE and CatG in a biological sample comprising contacting the biological sample with the composition containing the CBM polypeptide and the dye/label or a chemical entity comprising the anchor and the indicator comprising the CBM polypeptide and the dye/label; and detecting the label.
  • a method for the determining the presence or absence of an enzyme selected from the group consisting of HLE and CatG in a biological sample comprising contacting the biological sample with the composition containing the PDM polypeptide and the dye/label or a chemical entity comprising the anchor and the indicator comprising the PDM polypeptide and the dye/label; and detecting the label.
  • a method for diagnosing an infected or a chronic wound comprising, contacting the wound with the composition containing the CBM polypeptide and the dye/label or a chemical entity comprising the anchor and the indicator comprising the CBM polypeptide and the dye/label; and detecting the label.
  • the wound is present in a tissue, e.g., skin tissue, of a subject in need of such diagnosis, e.g., a human subject.
  • the detection is made in situ.
  • the diagnosis can be at multiple time points, based on visual and/or electronic valuation of the dye.
  • a method for diagnosing an infected or a chronic wound comprising, contacting the wound with the composition containing the PDM polypeptide and the dye/label or a chemical entity comprising the anchor and the indicator comprising the CBM polypeptide and the dye/label; and detecting the label.
  • the wound is present in a tissue, e.g., skin tissue, of a subject in need of such diagnosis, e.g., a human subject.
  • the detection is made in situ.
  • the diagnosis can be at multiple time points, based on visual and/or electronic valuation of the dye.
  • a method for treating an infected or a chronic wound comprising, contacting the wound with any of the foregoing compositions, wherein the composition comprises at least one antibiotic and optionally together with a healing agent.
  • the wound to be treated is present in a tissue, e.g., skin tissue, of a subject in need of such diagnosis, e.g., a human subject.
  • the wound is treated in situ and may be accompanied by pre-treatment or post-treatment diagnosis.
  • a polypeptide comprising the sequence set forth in (a) X y AAPX y -Z , (b) X y AAPX y -L-Z , (c) X y AAP(V/F/A)X y - Z , or (d) X y AAP(V/F/A)X y -L-Z , wherein each X is independently any amino acid, y is each, independently, an integer between 0 and 200, L is a linking moiety, and Z comprises a detectable label.
  • a polypeptide comprising the sequence set forth in (a) X y AAPX y -Z , (b) X y AAPX y -L-Z , (c) X y AAP(V/F/A)X y - Z , or (d) X y AAP(V/F/A)X y -L-Z , wherein each X is independently any amino acid, y is each, independently, an integer between 1 and 50, L is a linking moiety, and Z comprises a detectable label.
  • a polypeptide comprising the sequence set forth in (a) X y AAPX y -Z , (b) X y AAPX y -L-Z , (c) X y AAP(V/F/A)X y - Z , or (d) X y AAP(V/F/A)X y -L-Z , wherein each X is independently any amino acid, y is each, independently, an integer between 1 and 10, L is a linking moiety, and Z comprises a detectable label.
  • a polypeptide comprising the sequence set forth in (a) X y AAPX y -Z , (b) X y AAPX y -L-Z , (c) X y AAP(V/F/A)X y - Z , or (d) X y AAP(V/F/A)X y -L-Z , wherein each X is independently any amino acid, y is each, independently, an integer between 1 and 6, L is a linking moiety, and Z comprises a detectable label.
  • a polypeptide comprising the sequence set forth in (a) X y AAPX y -Z , (b) X y AAPX y -L-Z , (c) X y AAP(V/F/A)X y - Z , or (d) X y AAP(V/F/A)X y -L-Z , wherein each X is independently any amino acid, y is each, independently, an integer between 0 and 200, L is a linking moiety, and Z comprises a detectable label, wherein each of the peptides comprising the sequence X y AAPX y -Z , X y AAPX y -L-Z , X y AAP(V/F/A)X y -Z or X y AAP(V F/A)X y -L-Z , are each, individually, labile to elastase.
  • composition comprising a polypeptide comprising the sequence set forth in (a) X y AAPX y -Z , (b) X y AAPX y -L-Z , (c) X y AAP(V/F/A)X y - Z , or (d) X y AAP(V/F/A)X y -L-Z , wherein each X is independently any amino acid, y is each, independently, an integer between 0 and 200, L is a linking moiety, and Z comprises a detectable label, and a carrier.
  • a chemical entity comprising an anchor region (A) and an indicator region (I) comprising a polypeptide comprising the sequence set forth in (a) X y AAPX y -Z , (b) X y AAPX y -L-Z , (c) X y AAP(V/F/A)X Z , or (d) X y AAP(V/F/A)X y -L-Z , wherein each X is independently any amino acid, y is each, independently, an integer between 0 and 200, L is a linking moiety, and Z comprises a detectable label.
  • a polypeptide comprising the amino acid sequence set forth in (a) X N 4 N 3 N 2 N -Z , or (b) X N 4 N 3 N 2 N -E-Z , wherein X is each, independently any amino acid; y is each, independently, a number selected from 0 to 6; N 4 is selected from alanine, glycine, valine, and glutamine; N 3 is selected from alanine, glycine, proline, lysine, and serine ; N 2 is selected from proline, alanine, and glycine; N 1 is selected from serine, lysine, phenylalanine, arginine, leucine, and methionine; L is a linking moiety; and Z comprises a detectable label.
  • a polypeptide comprising the amino acid sequence set forth in (a) X N 4 N 3 N 2 N3 ⁇ 4-Z, or (b) X y N 4 N 3 N 2 N 1 X Y -L-Z , wherein X is each, independently any amino acid; y is each, independently, a number selected from 1 to 3; N 4 is selected from alanine, glycine, valine, and glutamine; N 3 is selected from alanine, glycine, proline, lysine, and serine ; N 2 is selected from proline, alanine, and glycine; N 1 is selected from serine, lysine, phenylalanine, arginine, leucine, and methionine; L is a linking moiety; and Z comprises a detectable label.
  • a polypeptide comprising the amino acid sequence set forth in (a) X y N 4 N 3 N 2 N 1 X y -Z , or (b) X y N 4 N 3 N 2 N 1 X Y -L-Z , wherein X is each, independently any amino acid; y is each, independently, a number selected from 0 to 6; N 4 is selected from alanine, glycine, valine, and glutamine; N 3 is selected from alanine, glycine, proline, lysine, and serine ; N 2 is selected from proline, alanine, and glycine; N 1 is selected from serine, lysine, phenylalanine, arginine, leucine, and methionine; L is a linking moiety; and Z comprises a detectable label, wherein the polypeptides comprising the sequence (a) X y N 4 N 3 N 2 N 1 X y -
  • composition comprising a polypeptide comprising the amino acid sequence set forth in (a) X y N ⁇ N ⁇ X y -Z , or (b) X y N ⁇ N ⁇ X y -L-Z , wherein X is each, independently any amino acid; y is each, independently, a number selected from 0 to 6; N 4 is selected from alanine, glycine, valine, and glutamine; N 3 is selected from alanine, glycine, proline, lysine, and serine ; N 2 is selected from proline, alanine, and glycine; N 1 is selected from serine, lysine, phenylalanine, arginine, leucine, and methionine; L is a linking moiety; and Z comprises a detectable label and a carrier.
  • a chemical entity comprising an anchor region (A) and an indicator region (I) comprising a polypeptide comprising the amino acid sequence set forth in (a) X y N 4 N 3 N 2 N 1 X y -Z, or (b) X y N 4 N 3 N 2 N 1 X y -L-Z , wherein X is each, independently any amino acid; y is each, independently, a number selected from 0 to 6; N 4 is selected from alanine, glycine, valine, and glutamine; N 3 is selected from alanine, glycine, proline, lysine, and serine; N 2 is selected from proline, alanine, and glycine; N 1 is selected from serine, lysine, phenylalanine, arginine, leucine, and methionine; L is a linking moiety; and Z comprises a detectable label.
  • FIG. 1 Infrared spectrum of Example 2. Chitosan derivatives with varying degree of acetylation (DA) were produced, but only material with a DA of 48% was further used.
  • DA acetylation
  • FIG. 2 Infrared spectrum and NMR spectrum of Example 2. Chitosan derivatives with varying DA were produced, but only material with a DA of 48% was further used.
  • FIG. 3 Infrared spectrum of chitooligosaccharides of Example 5.
  • FIG. 4 Infrared spectrum of chitooligosaccharides of Example 6.
  • FIG. 5 Time course of dye release from dye conjugated acetyl chitosan when incubated with 5000 units per mL lysozyme.
  • FIG. 6 (A) Time course of dye release from dye conjugated acetyl chitosan when incubated with 5000 units per mL lysozyme in phosphate buffer when the chitosan has varying concentrations of dye conjugated; (B) Time course of dye release from dye conjugated acetyl chitosan when incubated with 5000 units per mL lysozyme in either phosphate buffer of artificial wound fluid containing 2% protein as BSA.
  • FIG. 7 Color response of immobilized nitrazine yellow and bromocresol purple of Example 11 varies depending on the pH at which the preparation is dried.
  • FIG. 8 Comparison of different lysozyme responsive dye releases of different staining degrees.
  • FIG. 9 Influence of the proportion between reactive dye and PG.
  • FIG. 10 Elastase responsive dye release.
  • FIG. 11 Multiple Sequence Alignment of the Various Constructs.
  • Asterisk (*) indicates identity; semi -colon (:) indicates conservative substitution; and period (.) indicates semi-conservative substitution.
  • “Substantially” or “essentially” means nearly totally or completely, for instance, 80%-95% or greater of some given quantity, e.g., at least 85%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.9%, or more % by weight or volume or any other parameter being measured.
  • “Substantially free” means nearly totally or completely absent of some given quantity such as being present at a level of less than about 1% to about 20% of some given quantity, e.g., less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%), less than 0.1%, or less % by weight or volume or any other parameter being measured.
  • “substantially free” means presence at a level of less than or equal to 1 -5% by weight of the pharmaceutical composition.
  • compositions and systems for the therapy and diagnosis of wounds and wound management wherein the compositions, when in use, indicate the presence of elevated enzyme levels in a wound in situ.
  • wound refers to physical disruption of the continuity or integrity of tissue structure.
  • Wild healing refers to the restoration of tissue integrity. It will be understood that this can refer to a partial or a full restoration of tissue integrity. Treatment of a wound thus refers to the promotion, improvement, progression, acceleration, or otherwise advancement of one or more stages or processes associated with the wound healing process.
  • the wound may be acute or chronic.
  • Chronic wounds including pressure sores, venous leg ulcers and diabetic foot ulcers, can simply be described as wounds that fail to heal. Whilst the exact molecular pathogenesis of chronic wounds is not fully understood, it is acknowledged to be multi -factorial. As the normal responses of resident and migratory cells during acute injury become impaired, these wounds are characterized by a prolonged inflammatory response, defective wound extracellular matrix (ECM) remodeling and a failure of re-epithelialization.
  • ECM extracellular matrix
  • the wound may be any internal wound, e.g., where the external structural integrity of the skin is maintained, such as in bruising or internal ulceration, or external wounds, particularly cutaneous wounds, and consequently the tissue may be any internal or external bodily tissue.
  • the tissue is skin (such as human skin), i.e. the wound is a cutaneous wound, such as a dermal or epidermal wound.
  • the human skin is composed of two distinct layers, the epidermis and the dermis, below which lies the subcutaneous tissue.
  • the primary functions of the skin are to provide protection to the internal organs and tissues from external trauma and pathogenic infection, sensation and thermoregulation.
  • the skin tissue of most mammals is structured similarly.
  • the outermost layer of skin, the epidermis is approximately 0.04 mm thick, is avascular, is comprised of four cell types (keratinocytes, melanocytes, Langerhans cells, and Merkel cells), and is stratified into several epithelial cell layers.
  • the inner-most epithelial layer of the epidermis is the basement membrane, which is in direct contact with, and anchors the epidermis to, the dermis. All epithelial cell division occurring in skin takes place at the basement membrane. After cell division, the epithelial cells migrate towards the outer surface of the epidermis. During this migration, the cells undergo a process known as keratinization, whereby nuclei are lost and the cells are transformed into tough, flat, resistant non-living cells.
  • Migration is completed when the cells reach the outermost epidermal structure, the stratum corneum, a dry, waterproof squamous cell layer which helps to prevent desiccation of the underlying tissue.
  • This layer of dead epithelial cells is continuously being sloughed off and replaced by keratinized cells moving to the surface from the basement membrane. Because the epidermal epithelium is avascular, the basement membrane is dependent upon the dermis for its nutrient supply.
  • the dermis is a highly vascularized tissue layer supplying nutrients to the epidermis.
  • the dermis contains nerve endings, lymphatics, collagen protein, and connective tissue.
  • the dermis is approximately 0.5 mm thick and is composed predominantly of fibroblasts and macrophages. These cell types are largely responsible for the production and maintenance of collagen, the protein found in all animal connective tissue, including the skin. Collagen is primarily responsible for the skin’s resilient, elastic nature.
  • the subcutaneous tissue, found beneath the collagen-rich dermis provides for skin mobility, insulation, calorie storage, and blood to the tissues above it.
  • Wounds can be classified in one of two general categories, partial thickness wounds or full thickness wounds.
  • a partial thickness wound is limited to the epidermis and superficial dermis with no damage to the dermal blood vessels.
  • a full thickness wound involves disruption of the dermis and extends to deeper tissue layers, involving disruption of the dermal blood vessels.
  • the healing of the partial thickness wound occurs by simple regeneration of epithelial tissue. Wound healing in full thickness wounds is more complex. Cutaneous wounds contemplated herein may be either partial thickness or full thickness wounds.
  • Wounds contemplated herein include cuts and lacerations, surgical incisions or wounds, punctures, grazes, scratches, compression wounds, abrasions, friction wounds (e.g., nappy rash, friction blisters), decubitus ulcers (e.g., pressure or bed sores); thermal effect wounds (burns from cold and heat sources, either directly or through conduction, convection, or radiation, and electrical sources), chemical wounds (e.g.
  • pathogenic infections e.g., viral, bacterial or fungal
  • pathogenic infections including open or intact boils, skin eruptions, blemishes and acne, ulcers, chronic wounds, (including diabetic-associated wounds such as lower leg and foot ulcers, venous leg ulcers and pressure sores), skin graft/transplant donor and recipient sites, immune response conditions, e.g., psoriasis and eczema, stomach or intestinal ulcers, oral wounds, including a ulcers of the mouth, damaged cartilage or bone, amputation wounds and corneal lesions.
  • Embodiments described herein provide chemical entities, which may be used to diagnose and/or treat chronic wounds.
  • the chemical entities and compositions thereof, as described herein are used in methods to detect the level of one or more enzymes in a mammalian wound.
  • the chemical entities and compositions thereof, as described herein are used in methods to diagnose a chronic wound in a mammal.
  • the chemical entities and compositions thereof described herein are used in methods to diagnose an infected wound in a mammal.
  • the chemical entities and compositions thereof described herein are used in methods to treat a wound in a mammal.
  • the chemical entities and compositions thereof described herein are used in methods to treat an infected or a chronic wound in a mammal.
  • a chemical entity capable of detecting enzyme activity from a body fluid, the chemical entity comprising: an anchor region (A) and an indicator region (I).
  • the chemical entity has a basic chemical structure A-I (Formula I), wherein A is an anchor region and I is an indicator region.
  • the anchor region (A) is associated with the indicator region (I) via an enzyme recognition site (S).
  • the enzyme recognition site is a structure or a motif that allows binding to an enzyme.
  • the enzyme recognition site (S) is naturally present in the anchor region. In another embodiment, the enzyme recognition site (S) is introduced in the anchor region via chemical modification. Alternately, the enzyme recognition site (S) may be naturally present in the indicator region (I) or synthetically introduced in the indicator region (I) via one or more chemical modifications.
  • the chemical entity of Formula I comprises an anchor (A) which is associated with the indicator (I), either covalently or non-covalently.
  • the association between the anchor region (A) and the indicator region (I) is mediated via a covalent interaction.
  • covalent bonds involve sharing of electrons between the bonded atoms.
  • non-covalent bonds may include, for example, ionic interactions, electrostatic interactions, hydrogen bonding interactions, physiochemical interactions, van der Waal forces, Lewis-acid/Lewis-base interactions, or combinations thereof.
  • the anchor A is associated with the indicator I via a covalent interaction to form the recognition site S. In another embodiment, the anchor A is associated with the indicator I via a covalent interaction that is not a part of the recognition site S.
  • the chemical entity further comprises an enzyme-labile or enzyme-reactive region (R).
  • the reactive region (R) is a part of the anchor region.
  • the reactive region (R) is a part of the indicator region (I).
  • the reactive region (R) is a part of the enzyme recognition site (S).
  • the reactive region (R) interacts with one or more target enzymes selected from the group consisting of elastase, lysozyme, cathepsin G, and myeloperoxidase, or a combination thereof.
  • the anchor region comprises a compound which is a polysaccharide, cellulose, polyacrylate, polyethyleneimine, polyacrylamide, peptidoglycan, or chitosan, or a monomer thereof, a derivative thereof, a mixture or a combination thereof.
  • the anchor A comprises a compound which is a chitosan or a monomer thereof, a derivative thereof, a mixture or a combination thereof.
  • Non-covalent bonds may include, for example, ionic interactions, electrostatic interactions, hydrogen bonding inetyl-D-glucosamine (acetylated unit).
  • chitosan monomer may comprise D-glucosamine and N-acetyl-D-glucosamine.
  • the chitosan may comprise at least 2, at least 3, at least 4, at least 5, or more units of D-glucosamine or N-acetyl-D-glucosamine or a combination thereof.
  • Chitosan, including, shorter fragments thereof is generally manufactured by treating chitin with an alkaline substance, e.g., sodium hydroxide, and optionally hydrolyzing the glycosidic linkages between the individual monomer units.
  • the anchor A comprises a chitosan derivative.
  • Example chitosan or chitosan derivatives include chitosan salts, water-soluble chitosan, water-soluble, randomly substituted partial N-, partial O-acetylated chitosan, chitosan oligosaccharide, carboxymethyl chitosan, and hydroxyalkyl chitosan.
  • the hydroxyalkyl substituents of the hydroxyalkyl, chitosans and the carboxym ethyl substituents of the carboxy methyl chitosans could be attached to any of the pendant nitrogen or oxygen groups on the chitin or chitosan ring subunit.
  • hydroxyalkyl chitosans include but are not limited to, hydroxyethyl chitosan (also known as glycol chitosan), hydroxypropyl chitosan, dihydroxypropyl chitosan, hydroxybutyl chitosan and dihydroxybutyl chitosan.
  • the chitosan derivative is a randomly substituted partial N-, partial O-acetylated chitosan.
  • the acetylated chitosan derivatives are generally defined by a degree of acetylation or degree of acetylation.
  • the degree of acetylation represents the proportion of N-acetyl-d-glucosamine units with respect to the total number of units in the chitosan molecule. See, Chatelet et al., Biomaterials , 22(3):261-8, 2001.
  • degree of deacetylation is meant the percentage of free amino groups on the water soluble, chitosan or chitosan derivative.
  • the percent of N-acetylation can be calculated from the deacetylation value.
  • N-acetylation or O-acetylation are also referred to as the degree of substitution with C(0)CH 3 on either N or O.
  • a chitosan derivative having a DA value greater than 50% N-acetylation is sometimes described as a chitin.
  • the term “chitosan” is used throughout the disclosure herein to include chitosans and, if the N-acetylation is greater than 50%, to include chitins. See, U.S. Pat. No. 7,683,039.
  • the chitosan derivative has a DA of at least about 40%, about 41%, about 42%, about 43%, about 44%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about
  • chitosan derivative as used herein includes salts, amides, esters, enol ethers, enol esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, solvates, hydrates or prodrugs of the chitosan.
  • Such derivatives may be readily prepared by those of skill in this art using known methods for such derivatization.
  • the derivatives may be administered to animals or humans without substantial toxic effects and either are pharmaceutically active or are prodrugs. Representative types of chitosan derivatives are described in U.S. Pat. Nos. 9,012,429; 5,773,608; and 3,911,116.
  • the derivative is a salt of the polymeric compound, e.g., salts of Li + , Na + , K + , Rb + , Mg 2+ , Ca 2+ , Sr 2+ , or Ba 2+ , preferably Na + , K + , Mg 2+ , Ca + .
  • Salts of chitin and chitosan, such as sodium or calcium salts, are known in the art. See, U.S. Pat. No. 5,599,916.
  • the derivative anchor compound is a halogenated anchor compound, e.g., halogenated polysaccharide, halogenated cellulose, halogenated polyacrylate, halogenated polyethyleneimine, halogenated polyacrylamide, halogenated peptidoglycan, or halogenated chitosan, or a monomer thereof, e.g., halogenated D-glucosamine and/or halogenated N-acetyl -D-glucosamine.
  • the halogen is selected from the group consisting of CI, Br, I; particularly, the halogen is CI.
  • the derivative compound is an isomer of the anchor compound
  • term “isomer” includes compounds with the same formula but a different arrangement of atoms in the molecule.
  • isomers of the compounds are “tautomers” or “stereoisomers” of the compounds.
  • stereoisomer refers to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers.
  • tautomer refers to alternate forms of a compound that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of the anchor compound.
  • the anchor compound may contain a combination or mixture of one or more of the aforementioned compounds.
  • the term “combination” includes compounds containing more than one component, which may be conjugated or non-conjugated to one another.
  • the anchor compound comprises a combination of one or more of the aforementioned compounds which are conjugated to each other, e.g., via covalent or non-covalent interaction.
  • the anchor may comprise a combination of chitosan and oxidized cellulose. See, U.S. Pat. Application Publication No. 2014/0045761.
  • the compounds include mixtures of the aforementioned polymeric compounds.
  • the term “mixture” refers to a mingling together of two or more substances without the occurrence of a reaction by which they would lose their individual properties.
  • a mixture of compound A and compound B may contain any weight ratio of compound A and compound B, such that the total weight of the mixture would amount to 100%, e.g., 99: 1 weight ratio of compound A/compound B or 1 :99 weight ratio of compound A/compound B.
  • a typical mixture may contain about 2, 3, 4, 5, or more of the aforementioned polymer compounds.
  • the anchor A further comprises an ionic chemical group, a material with a hydrophilic moiety, or a material with a hydrophobic moiety, e.g., an aliphatic chain or an aliphatic alcohol.
  • the anchor comprises an ionic chemical group
  • the ionic chemical group may be positively or negatively charged.
  • the anchor region comprises a reactive moiety for covalent attachment to a support material such as a photoactive phenylazide or an epoxide group. See, U.S. Pat. Application Publication No. 2016/0159777.
  • the chemical entities comprise one or more indicators, e.g., at least 1, at least 2, at least 3, at least 4, or more of indicators.
  • Such compositions may include, for example, a plurality of substrates conjugated to the same gel polymer or different gel polymers.
  • the indicators are labeled.
  • label refers to any substance attached to an epitope binding agent, or other substrate material, in which the substance is detectable by a detection method.
  • suitable labels include luminescent molecules, chemiluminescent molecules, fluorochromes, fluorescent quenching agents, colored molecules, radioisotopes, scintillants, biotin, avidin, streptavidin, protein A, protein G, antibodies or fragments thereof, polyhistidine, Ni2+, Flag tags, myc tags, heavy metals, and enzymes (including alkaline phosphatase, peroxidase, and luciferase). Methods for attaching the labels to the anchor compounds are described in the Examples.
  • the indicators are labeled with a label which is a detectable label.
  • a detectable label is a moiety, the presence of which can be ascertained directly or indirectly.
  • detection of the label involves the creation of a detectable signal such as for example an emission of energy.
  • the label may be of a chemical, peptide or nucleic acid nature although it is not so limited. The nature of label used will depend on a variety of factors, including the nature of the analysis being conducted, the type of the energy source and detector used and the type of polymer, analyte, probe and primary and secondary analyte-specific binding partners.
  • the label is sterically and chemically compatible with the constituents to which it is bound, e.g., the anchor region.
  • the label is of the shape and size that it does not hinder enzyme recognition site (S) and/or enzyme-reactive region (R).
  • the indicator or a motif therein attached to the anchor is a substrate for a glycosidase.
  • the indicator or motif therein attached to the anchor is a substrate for lysozyme.
  • the indicator or a motif therein attached to the anchor is a substrate for a protease selected from the group consisting of elastase, cathepsin G or myeloperoxidase (MAO), or a combination thereof.
  • a protease selected from the group consisting of elastase, cathepsin G or myeloperoxidase (MAO), or a combination thereof.
  • the indicator or a motif therein attached to the anchor is a substrate for a glycosidase which is lysozyme and a protease selected from the group consisting of elastase, cathepsin G or myeloperoxidase (MAO), or a combination thereof.
  • a glycosidase which is lysozyme and a protease selected from the group consisting of elastase, cathepsin G or myeloperoxidase (MAO), or a combination thereof.
  • the indicator (I) or a motif therein attached to the anchor is a peroxidase substrate, an arylamine, an amino phenol, an aminophenyl ether, an indoxyl, a neutral dye, a charged dye, a nanoparticle, or a colloidal gold particle.
  • the indicator (I) or a motif therein attached to the anchor is a peroxidase substrate.
  • the peroxidase substrate is selected from p-aminophenol, ABTS (2,2inophenol, ABTS (strate.
  • acid) diammonium salt 3,3′-diaminobenzidine, 3,4 diaminobenzoic acid, DCPIP, N,N dimethyl-p-phenylenediamine, o-dianisidine, /?-phenylenediamine, 4-chloro-l-naphthol, o-phenylenediamine N-(4-aminobutyl)-N-ethylisoluminol, 3-amino-9-ethylcarbazole, 4-aminophthalhydrazide, 5-aminosalicylic acid, 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid), indoxyl, indigo, Fast Blue RR, 4-chloro-7-nitrobenzofurazan.
  • the indicator (I) or a label attached thereto is an arylamine. In some embodiments, the indicator (I) or a label attached thereto is an amino phenol. In some embodiments, the indicator (I) or a label attached thereto is an aminophenol ether. In some embodiments, the indicator (I) or a label attached thereto is an indoxyl. In some embodiments, the indicator (I) or a label attached thereto is a neutral dye. In some embodiments, the indicator (I) or a label attached thereto is a charged dye.
  • the charged dye is selected from remazole brilliant blue, toluidine blue, reactive black 5, remazol brilliant blue, reactive violet 5, and reactive orange 16, or a hydrolytic or ammonolytic derivatives thereof.
  • the charged dye is remazole brilliant blue, or a hydrolytic or ammonolytic derivatives thereof.
  • the charged dye is toluidine blue.
  • the charged dye is reactive black 5, or ahydrolytic or ammonolytic derivatives thereof.
  • the charged dye is reactive violet 5, or hydrolytic or ammonolytic derivatives thereof.
  • the charged dye is reactive orange 16, or hydrolytic or ammonolytic derivatives thereof.
  • the indicator (I) or a label attached thereto is a dichlorotriazine-based reactive dye such as reactive blue 4, reactive red 120, reactive blue 2, reactive green 19 and reactive brown 10. In some embodiments, the dichlorotriazine-based reactive dye appears black.
  • the indicator (I) or a label attached thereto is a reactive dye containing a sulfonyl ethyl -hydrogensulphate-reactive-group.
  • the reactive dye is reactive black 5, remazol brilliant blue, reactive violet 5 or reactive orange 16.
  • the reactive dye is reactive black 5.
  • the reactive dye is remazol brilliant blue.
  • the reactive dye is reactive violet 5.
  • the reactive dye is reactive orange 16.
  • the reactive dye is reactive black 5, remazol brilliant blue, or reactive violet 5.
  • the reactive dye is reactive black 5 or remazol brilliant blue.
  • the indicator (I) or a label attached thereto is a nanoparticle. In some embodiments, the indicator (I) or a label attached thereto is a colloidal gold particle. In some embodiments, the indicator (I) or a label attached thereto is a charged dye, an indole derivative, or a luminol derivative.
  • the indicator or a motif therein attached to the anchor comprises a dye containing a sulfonyl ethyl -hydrogensulphate-reactive-group, e.g., reactive black 5, remazol brilliant blue, reactive violet 5 or reactive orange 16, or a combination thereof; or a dye containing a dichlortriazine reactive-group, e.g., reactive blue 4, reactive red 120, reactive blue 2, reactive green 19 and reactive brown 10, or a combination thereof.
  • a dye containing a sulfonyl ethyl -hydrogensulphate-reactive-group e.g., reactive black 5, remazol brilliant blue, reactive violet 5 or reactive orange 16, or a combination thereof
  • a dye containing a dichlortriazine reactive-group e.g., reactive blue 4, reactive red 120, reactive blue 2, reactive green 19 and reactive brown 10, or a combination thereof.
  • an anchor A is conjugated with the indicator I directly, e.g., via an glycosidic linkage.
  • the indicator is selected from the group consisting of reactive black 5, remazol brilliant blue, reactive violet 5 or reactive orange 16, reactive blue 4, reactive red 120, reactive blue 2, reactive green 19 and reactive brown 10, or a combination thereof.
  • a glycosidic linkage is formed between a hydroxyl group of the anchor compound with a reactive group in the indicator compound.
  • the la-carbon in the sugar backbone of the anchor molecule is involved in the glycosidic linkage.
  • Embodiments described herein may utilize chemical moieties that assay for various biological markers present in a chronic or infected wound.
  • the marker is a wound- specific marker, which is an enzyme selected from the group consisting of hydrolases, proteases, esterases, and peroxidases.
  • a “wound specific enzyme” is an enzyme that is differentially expressed in a wound.
  • differential expression it is meant that the level or the activity of the enzyme is higher or lower in the wound microenvironment compared to other sites, e.g., normal tissue or surrounding tissue. Particularly, differential expression implies higher level of expression or activity of the enzyme in the wound microenvironment compared to normal or unwounded tissue.
  • Differential expression of enzyme may be analyzed by routine means. For example, levels of enzyme in a sample may be analyzed by ELISA assays or other immunoassays. Activities of the enzyme may be analyzed by measuring rates of loss of a substrate and/or rates of formation of the product, e.g., using mass spectroscopy or HPLC. Such techniques are known in the art and are described in the Examples section.
  • the marker is a hydrolase.
  • a “hydrolase” or “hydrolytic enzyme” is an enzyme that catalyzes the hydrolysis of a chemical bond, e.g., esterases and nucleases (break ester bonds); glycolases (break glycosidic linkers); peptidases (break peptide bonds), etc.
  • the wound-specific glycoside hydrolase is lysozyme.
  • Lysozyme (UNIPROT accession Nos. P61626 [human] and P08905 [mouse]) is a glycoside hydrolase and its main function is to destroy the cell walls of bacteria. It hydrolyses the (1 ⁇ 4)- ⁇ -linkages between N-acetylmuramic acid and N-acetyl-D-glucosamine residues in peptidoglycan and also between N-acetyl-D glucosamine residues in chitodextrin.
  • the natural substrate for lysozyme is the peptidoglycan layer of bacterial cell walls.
  • the individual components of the chemical moiety have been adapted for recognition by wound-specific hydrolase, e.g., a wound-specific lysozyme.
  • the individual components of the chemical moiety can be modified for recognition by other wound specific enzymes.
  • the additional wound specific enzyme is a protease.
  • a “wound specific protease” is a protease that is differentially expressed in a wound.
  • differential expression it is meant that the level or the activity of the protease is higher or lower in the wound microenvironment compared to other sites, e.g., normal tissue or surrounding tissue.
  • differential expression implies higher level of expression or activity of the protease in the wound microenvironment compared to unwounded tissue. Differential expression of proteases may be analyzed by routine means.
  • levels of proteases in a sample may be analyzed by ELISA assays or other immunoassays. Activities of the proteases may be analyzed by measuring rates of loss of a peptide substrate and/or rates of formation of the product, e.g., using mass spectroscopy or HPLC. Such techniques are known in the art and are described in the Examples section.
  • the wound-specific protease is cathepsin G (UNIPROT accession Nos. P08311 [human] and P28293 [mouse]), which is one of the three serine proteases of the chymotrypsin family that are stored in the azurophil granules.
  • Cathepsin G-specific substrates have the sequence Ala-Ala-Pro-Phe [SEQ ID NO: 41 or Ala-Ala-Pro-Met [SEQ ID NO: 51 (Sigma Aldrich Catalog Nos. S7388 and M7771).
  • the wound specific protease is elastase (e.g., human neutrophil elastase or HNE) (UNIPROT accession Nos. P08246 [human] and Q3UP87 [mouse]).
  • HNE is a serine proteinase in the same family as chymotrypsin and has broad substrate specificity. Secreted by neutrophils and macrophages during inflammation, it destroys bacteria and host tissue.
  • the substrate for detecting HNE has a core sequence Alanine-Alanine-Proline- Valine (AAPV) [SEQ ID NO: 31.
  • the substrate for HNE is Ala- Pro-Glu-Glu-Ile/[ SEQ ID NO: 6]Met-Arg-Arg-Gln [SEQ ID NO: 7](APEEI MRRQ) (Kasperkiewicz et al., PNAS USA, 111(7): 2518-2523, 2014; Korkmaz et al., Methods Mol Biol , 844: 125-138, 2012).
  • the wound-specific enzyme is peroxidase, more specifically, a myeloperoxidase (MPO).
  • MPO myeloperoxidase
  • H202 hydrogen peroxide
  • a halide most commonly chloride
  • hypochlorite singlet oxygen
  • chlorine C12
  • hydroxyl radicals OH ⁇
  • MPO can be detected using tetramethylbenzidine or 4-Benzoylamino-2,5-dimethoxyaniline. See, Andrews et al, Anal Biochem , 127(2):346-50, 1982; Klebanoff et al., J. Leukocyte Biol , 11, 598-625, 2005.
  • the chemical moiety comprises an anchor region A or an indicator (I) comprising a recognition site for a wound-specific enzyme, e.g., an enzyme cleavage site.
  • the enzyme recognition site comprises glycosidic bonds.
  • a “glycosidic bond” is formed between the hemiacetal or hemiketal group of a saccharide (or a molecule derived from a saccharide) and the hydroxyl group of some compound such as an alcohol.
  • a substance containing a glycosidic bond is a glycoside.
  • glycoside is now extended to also cover compounds with bonds formed between hemiacetal (or hemiketal) groups of sugars and several chemical groups other than hydroxyls, such as -SR (thioglycosides), -SeR (selenoglycosides), -NR1R2 (N-glycosides), or even -CR1R2R3 (C-glycosides).
  • the chemical moieties disclosed herein contain one or more glycosidic bonds which are cleaved by glycolases.
  • the chemical moieties comprise a glycosidic bond linking anchor A and the indicator I, either directly or via another group.
  • the anchor A and the indicator I are directly linked via one or more glycosidic bonds, in which case, the chemical entity is cleaved by the glycolase and therefore can be used in detecting the glycolase.
  • the indicator molecule comprises an enzymatically-cleavable peptide comprising a peptide bond.
  • a “peptide bond” is formed by the condensation reaction between two amino acids, wherein the acid moiety of one reacts with the amino moiety of the other to produce a peptide bond (—CO—NH—) between the two amino acids.
  • the individual peptides provide a motif for the recognition by a sequence-specific protease.
  • sequence-specific protease means a protease recognizing a specific sequence of a peptide for its digesting (for example, caspase), and is distinguished from a generic protease (for example, trypsin) that sequentially decomposes a peptide from one end thereof or digest a peptide in a sequence-nonspecific manner.
  • the amino acid sequence of the peptide substrate may comprise four or more amino acid (a.a.) residues.
  • peptide includes a natural peptide comprising a linear chain or branched amino acids, peptidomimetics, as well as pharmaceutically acceptable salts thereof.
  • a peptide comprises a plurality of amino acid residues, e.g., 2, 3, 4, 5, 6, 8, 10, or more amino acid residues which are bonded to each other via covalent bonds, e.g., a peptide bond.
  • Amino acid residue means the individual amino acid units incorporated into the peptides of the disclosure.
  • amino acid means a naturally occurring or synthetic amino acid, as well as amino acid analogs, stereoisomers, and amino acid mimetics that function similarly to the naturally occurring amino acids.
  • amino acids such as: (1) histidine (His) (2) isoleucine (He) (3) leucine (Leu) (4) ysine (Lys) (5) methionine (Met) (6) phenylalanine (Phe) (7) threonine (Thr) (8) tryptophan (Trp) (9) valine (Val) (10) arginine (Arg) (11) cysteine (Cys) (12) glutamine (Gin) (13) glycine (Gly) (14) proline (Pro) (15) serine (Ser) (16) tyrosine (Tyr) (17) alanine (Ala) (18) asparagine (Asn) (19) aspartic acid (Asp) (20) glutamic acid (Glu) (21) selenocysteine (Sec); including unnatural amino acids: (a) citrulline; (b) cystine; (c) gama-amino butyric acid (GAB A); (d)
  • amino acids containing reactive side chains e.g., cysteine, serine, threonine, lysine, arginine, aspartate/asparagine, glutamate/glutamine, glycine, alanine, etc. are particularly employed for modification of the substrate.
  • the chemical entities contain one or more enzyme-labile or enzyme-reactive regions (R) for the detection of wound-specific enzymes.
  • the enzyme-labile or enzyme-reactive region comprises an acyl chitosan of at least 3 glucosamine or N-acetylglucosamine or peptidoglycan units, which are optionally acetylated.
  • the enzyme reactive site may contain, for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 20 or more units of glucosamine or N-acetylglucosamine or peptidoglycan units.
  • the R comprises at least 3 glucosamine or N-acetylglucosamine or a combination thereof, wherein the glucosamine and/or N-acetylglucosamine are optionally acetylated.
  • the enzyme-labile or enzyme-reactive region comprises peptidoglycan, wherein the peptidoglycan is optionally acetylated.
  • the chemical moieties comprise enzyme reactive sites (R) for one or more wound-specific protease disclosed above, e.g., cathepsin G, and myeloperoxidase, elastase or a combination thereof.
  • R enzyme reactive sites
  • the term “reactive site for a protease” means a peptide comprising an amino acid sequence of a protein, which is recognized by the protease as a substrate for its protease activity, e.g., as a substrate that can be cleaved into one or more products.
  • the chemical entities comprise a peptide region comprising a peptide sequence comprising a plurality of amino acids.
  • the indicator region (I) of the chemical entity comprises the peptide which serves as the enzyme reactive site for the wound-specific protease.
  • the enzyme-labile or enzyme-reactive region comprises a peptide that is labile to elastase, cathepsin G, myeloperoxidase or a combination thereof.
  • the enzyme-labile region comprises a peptide that is liable to elastase.
  • the chromogenic indicator for elastase would be high contrast and thus serve as a clear indicator when used in situ in medicinal products.
  • the ideal substrate would make a blue, violet or deep green colour. It would also be fixed in a sterically permissible position with high turnover.
  • the state of the art is the opposite.
  • Available substrates contain a p-nitrophenol group, which is low molecular weight but gives rise to a yellow soluble chromophore.
  • Most skilled investigators regard that the substrate should be soluble in water, reasoning that this is the most likely way that the substrate will find its way to the active site.
  • embodiments described herein contemplate use of a low water soluble, elastase substrates that give rise to Blue, violet or Green colors.
  • the enzyme-labile or enzyme-reactive region comprises a peptide comprising an amino acid sequence of:
  • the enzyme-labile or enzyme-reactive region comprises a peptide comprising an amino acid sequence of:
  • the enzyme-labile or enzyme-reactive region comprises a peptide comprising an amino acid sequence of:
  • the enzyme-labile or enzyme-reactive region comprises a peptide comprising an amino acid sequence of:
  • the reactive region R comprises the peptide sequence X y AAPX y -Z , X y AAPX y -L-Z , X y AAP(V/F/A)X y -Z or X y AAP(V/F/A)X y -L-Z , wherein X, L and Z are each, as described above, and y is, each, independently an integer from 1 to 50.
  • the reactive region R comprises the peptide sequence X y AAPX Z , X y AAPX y -L-Z , X y AAP(V/F/A)X y -Z or X y AAP(V/F/A)X y -L-Z , wherein X, L and Z are each, as described above, and y is, each, independently an integer from 1 to 10.
  • the reactive region R comprises the peptide sequence X y AAPX y -Z , X y AAPX y -L-Z , X y AAP(V/F/A)X y -Z or X y AAP(V/F/A)X y -L-Z , wherein X, L and Z are each, as described above, and y is, each, independently an integer from 1 to 6.
  • each of the aforementioned peptides comprising the sequence X y AAPX y -Z , X y AAPX y -L-Z , X y AAP(V/F/A)X y -Z or X y AAP(V/F/A)X y -L-Z , are each, individually, labile to elastase.
  • one or more of the amino acids in the amino acid sequence X y AAPX y -Z , X y AAPX y -L-Z , X y AAP(V/F/A)X y -Z or X y AAP(V/F/A)X y -L-Z is protected, e . g . , with an amine protection group, for example, fluorenylmethyloxycarbonyl (Fmoc).
  • an amine protection group for example, fluorenylmethyloxycarbonyl (Fmoc).
  • the elastase substrates have the formula a-b-c-d-e-f, wherein
  • elastase substrates have the formula a-b-c-d-e-f, wherein
  • elastase substrates have the formula a-b-c-d-e-f, wherein
  • elastase substrates have the formula a-b-c-d-e-f, wherein
  • elastase substrates have the formula a-b-c-d-e-f, wherein
  • elastase substrates have the formula a-b-c-d-e-f, wherein
  • the enzyme-labile or enzyme-reactive region comprises a peptide that is labile to cathepsin G.
  • the enzyme-labile or enzyme-reactive region comprises a peptide comprising an amino acid sequence of:
  • one or more of the amino acids in the amino acid sequence is protected. In some embodiments, one or more of the amino acids in the amino acid sequence is protected with an fmoc group. In some embodiments, one of the amino acid in the amino acid sequence is protected with an fmoc group.
  • the enzyme-labile or enzyme-reactive region comprises a peptide comprising an amino acid sequence of
  • each of the aforementioned peptides comprising the sequence X y N 4 N 3 N 2 N 1 -Z and X y N 4 N 3 N 2 N 1 X y -L-Z , are each, individually, labile to cathepsin G.
  • one or more of the amino acids in the amino acid sequence X y N 4 N 3 N 2 N 1 X y -Z and X y N 4 N 3 N 2 N 1 X y -L-Z is protected, e.g., with an amine protection group, for example, fluorenylmethyloxycarbonyl (Fmoc).
  • an amine protection group for example, fluorenylmethyloxycarbonyl (Fmoc).
  • Z is a peroxidase substrate, an arylamine, an amino phenol, an aminophenyl ether, an indoxyl, a neutral dye, a charged dye, a nanoparticle, or a colloidal gold particle.
  • Z is a peroxidase substrate selected from p-aminophenol, ABTS (2,2inophenol, ABTS (s, the peroxidase substrate acid) diammonium salt), 3,3′-diaminobenzidine, 3,4 diaminobenzoic acid, DCPIP, N,N-dimethyl-p-phenylenediamine, o-dianisidine, >-phenylenediamine, 4-chloro-l-naphthol, o-phenylenedi amine N-(4-aminobutyl)-N-ethylisoluminol, 3-amino-9-ethylcarbazole, 4-aminophthalhydrazide, 5-aminosalicylic acid, 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid), indoxyl, indigo, Fast Blue RR, 4-chloro-7-nitrobenzofurazan.
  • Z is an arylamine, an amino phenol, an aminophenol ether, an indoxyl, a neutral dye, a charged dye selected from remazole brilliant blue, toluidine blue, reactive black 5, remazol brilliant blue, reactive violet 5, and reactive orange 16, or a hydrolytic or ammonolytic derivatives thereof.
  • Z is a charged dye selected from remazole brilliant blue; toluidine blue; reactive black 5 or a hydrolytic or an ammonolytic derivative thereof.
  • Z is a dichlorotriazine-based reactive dye such as reactive blue 4, reactive red 120, reactive blue 2, reactive green 19 and reactive brown 10. In some embodiments, the dichlorotriazine-based reactive dye appears black. In some embodiments, Z is a reactive dye containing a sulfonylethyl-hydrogensulphate-reactive-group.
  • Z is a nanoparticle. In some embodiments, Z is a colloidal gold particle.
  • Z is a charged dye, an indole derivative, or a luminol derivative.
  • the enzyme-labile or enzyme-reactive region comprises a phenol, an amino phenol, an aminophenyl ether, an indoxyl, or a quinone. In some embodiments, the enzyme-labile or enzyme-reactive region comprises a phenol. In some embodiments, the enzyme-labile or enzyme-reactive region comprises an amino phenol. In some embodiments, the enzyme-labile or enzyme-reactive region comprises an amino phenol ether. In some embodiments, the enzyme-label or enzyme-reactive region comprises an indoxyl. In some embodiments, the enzyme-labile or enzyme-reactive region comprises a quinone. In some embodiments, the enzyme-labile or enzyme-reactive region reacts with myeloperoxidase but does not react with heme.
  • the enzyme-labile or enzyme-reactive region comprises a peroxidase substrate, an arylamine, an amino phenol, a neutral dye, a charged dye, a nanoparticle, or a colloidal gold particle. In some embodiments, the enzyme-labile or enzyme-reactive region comprises a peroxidase substrate.
  • the peroxidase substrate is selected from p-aminophenol, ABTS (2,2-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt), 3,3′-diaminobenzidine, 3,4 diaminobenzoic acid, DCPIP, N,N-dimethyl-p-phenylenediamine, o-dianisidine, p-phenylenediamine, 4-chloro-l-naphthol, o- phenylenediamine N-(4-aminobutyl)-N-ethylisoluminol, 3-amino-9-ethylcarbazole, 4- aminophthalhydrazide, 5-aminosalicylic acid, 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid), and 4-chloro-7-nitrobenzofurazan, Fast Blue RR, N-(2-hydroxy)
  • the enzyme-labile or enzyme-reactive region comprises an arylamine. In some embodiments, the enzyme-labile or enzyme-reactive region comprises an amino phenol. In some embodiments, the enzyme-labile or enzyme-reactive region comprises a neutral dye. In some embodiments, the enzyme-labile or enzyme-reactive region comprises a charged dye. In some embodiments, the charged dye is selected from remazole brilliant blue, toluidine blue, reactive black 5, remazol brilliant blue, reactive violet 5, and reactive orange 16, or hydrolytic or ammonolytic derivatives of each of these. In some embodiments, the charged dye is remazole brilliant blue, or hydrolytic or ammonolytic derivatives thereof. In some embodiments, the charged dye is toluidine blue.
  • the charged dye is reactive black 5, or hydrolytic or ammonolytic derivatives thereof. In some embodiments, the charged dye is reactive violet 5, or hydrolytic or ammonolytic derivatives thereof. In some embodiments, the charged dye is reactive orange 16, or hydrolytic or ammonolytic derivatives thereof.
  • the enzyme-labile or enzyme-reactive region comprises a dichlorotriazine-based reactive dye such as reactive blue 4, reactive red 120, reactive blue 2, reactive green 19 and reactive brown 10.
  • the enzyme-labile or enzyme-reactive region comprises a nanoparticle.
  • Z is a colloidal gold particle.
  • the enzyme-labile or enzyme-reactive region comprises a charged dye, an indole derivative, or a luminol derivative. In some embodiments, the enzyme-labile or enzyme-reactive region comprises an indole derivative. In some embodiments, the enzyme-labile or enzyme-reactive region comprises a luminol derivative.
  • the indicator region comprises a dye that presents a visible color change in normal ambient lighting.
  • the dye has a contrasting color to wound products, which are commonly red, yellow, or brown.
  • the dye is violet, blue or dark green.
  • the dye is violet.
  • the dye is blue.
  • the dye is dark green.
  • the dye has low molecular weight, is charged, contains reactive or linkable groups, is stable to gamma irradiation, and is deeply colored.
  • the dye is selected from cibracron series dyes, azo dyes, and remazol dyes, or hydrolytic or ammonolytic derivatives thereof.
  • the dye is selected from cibracron series dyes. In some embodiments, the dye is selected from azo dyes. In some embodiments, the dye is selected from remazol dyes, or hydrolytic or ammonolytic derivatives thereof.
  • the dye is selected from rhodamine, coumarin, cyanine, xanthene, polymethine, pyrene, dipyrromethene borondifluoride, napthalimide, a phycobiliprotein, peridinium chlorophyll proteins, fluorescein, 6-FAM, rhodamine, Texas Red, California Red, iFluor594, tetramethylrhodamine, a carboxyrhodamine, carboxyrhodamine 6F, carboxyrhodol, carboxyrhodamine 110, Cascade Blue, Cascade Yellow, coumarin, Cy2®, Cy3®, Cy3.5®, Cy5®, Cy5.5®, Cy7®, Cy-Chrome, DyLight 350, DyLight 405, DyLight 488, DyLight 549, DyLight 594, DyLight 633, DyLight 649, DyLight 680, DyLight 750, DyL
  • the indicator region comprises a dichlorotriazine-based reactive dye such as reactive blue 4, reactive red 120, reactive blue 2, reactive green 19 and reactive brown 10. In some embodiments, the dichlorotriazine-based reactive dye appears black.
  • the indicator region comprises the reaction product of a reactive dye containing a sulfonylethyl-hydrogensulphate-reactive-group.
  • the reactive dye is reactive black 5, remazol brilliant blue, reactive violet 5 or reactive orange 16.
  • the reactive dye is reactive black 5.
  • the reactive dye is remazol brilliant blue.
  • the reactive dye is reactive violet 5.
  • the reactive dye is reactive orange 16.
  • the reactive dye is reactive black 5, remazol brilliant blue, or reactive violet 5.
  • the reactive dye is reactive black 5 or remazol brilliant blue.
  • the indicator region comprises a particle ⁇ e.g., colloidal metal or quantum dots) that present color changes in normal ambient lighting.
  • the indicator region comprises a nanoparticle.
  • the indicator region comprises a colloidal gold particle.
  • the indicator region comprises a dye that presents a visible color change under UV light. In some embodiments, the indicator region comprises a dye that is fluorescent. In some embodiments, the indicator region comprises a dye that is luminescent.
  • the indicator region comprises an enzyme-reactive moiety.
  • the enzyme-reactive moiety interacts with an accessory enzyme to produce a product that is visible to the naked eye or detectable by electronic means.
  • the enzyme-reactive moiety interacts with an accessory enzyme to produce a product that is visible to the naked eye.
  • the enzyme -reactive moiety interacts with an accessory enzyme to produce a product that is detectable by electronic means.
  • the indicator region comprises an indoxyl glycoside that is cleaved by hexaminidase, glucuronidase, glucosidase or galactosidase depending on the terminal sugar used, to produce indigo.
  • the indicator region comprises a phenol that is oxidized by an accessory enzyme to produce a visible product. In some embodiments, the indicator region comprises a phenol that is oxidized by laccase to produce a visible product. In some embodiments, the indicator region comprises a metallo motif that is detectable by electronic means. In some embodiments, the indicator region comprises a ferrocene or ferrocene analog that is detectable by electronic means.
  • the accessory enzyme is selected from lipase, esterase, hexosaminidase, peroxidase, oxidase, glycosidase, glucosidase, and laccase. In some embodiments, the accessory enzyme is not present in the wound fluid. In some embodiments, the accessory enzyme is present in the wound fluid. In some embodiments, the enzyme-reactive moiety interacts with an accessory enzyme to produce a product that is visible under UV light.
  • chemical entities containing the anchor A, the indicator I which individually or together comprise a plurality of enzyme recognition sites (S) and enzyme reaction group (R).
  • S enzyme recognition sites
  • R enzyme reaction group
  • such chemical entities are employed to assay for a plurality of enzymes, e.g., a combination comprising at least one protease and at least one glycosidase.
  • chemical entities containing the anchor A, the indicator I which individually or together comprise a plurality of enzyme recognition sites (S) and enzyme reaction sites (R), wherein at least one reactive site is specific for a glycosidase, e.g., lysozyme; and at least one enzyme reaction site is specific for a protease selected from the group consisting of elastase, cathepsin G, myeloperoxidase or a combination thereof.
  • S enzyme recognition sites
  • R enzyme reaction sites
  • chemical entities containing the anchor A, the indicator I which individually or together comprise a plurality of enzyme recognition sites (S) and enzyme reaction sites (R), wherein at least one reactive site is specific for a glycosidase, e.g., lysozyme; and at least one enzyme reaction site is specific for a protease selected from the group consisting of elastase.
  • S enzyme recognition sites
  • R enzyme reaction sites
  • chemical entities containing the anchor A, the indicator I which individually or together comprise a plurality of enzyme recognition sites (S) and enzyme reaction sites (R), wherein at least one reactive site is specific for a glycosidase, e.g., lysozyme; and at least one enzyme reaction site is specific for a protease selected from the group consisting of cathepsin G.
  • S enzyme recognition sites
  • R enzyme reaction sites
  • chemical entities containing the anchor A, the indicator I which individually or together comprise a plurality of enzyme recognition sites (S) and enzyme reaction sites (R), wherein at least one reactive site is specific for a glycosidase, e.g., lysozyme; and at least one enzyme reaction site is specific for a protease selected from the group consisting of myeloperoxidase (MPO).
  • S enzyme recognition sites
  • R enzyme reaction sites
  • MPO myeloperoxidase
  • the diagnostic utility of chemical entities comprising a plurality of reaction and recognition sites will be greatly enhanced compared to entities comprising unitary (e.g., single type) of reaction and recognition sites.
  • entities comprising a plurality of reaction/recognition sites will permit diagnosis of at least 2, at least 3, at least 4 or more markers simultaneously.
  • lysosomal and protease activity at the wound situs may be detected and monitored simultaneously using the multiplex chemical entities disclosed herein.
  • the anchor region (A) of the chemical entity binds the chemical entity to a support material, e.g., via covalent interaction, ionic interaction, hydrophobic interaction, electrostatic interactions, hydrogen bonding interactions, physiochemical interactions, van der Waal forces, Lewis-acid/Lewis-base interactions, or combinations thereof.
  • the support matrix comprises dextran, agarose, silica, synthetic polymer, or dextran, agarose, silica, or synthetic polymer covalently coupled to an antibody, ligand, or epitope tag.
  • the anchor region is a polystyrene bead, silica gel bead, polysaccharide bead, polyacrylamide bead, cellulose bead, polysaccharide, derivatized cellulose, polyacrylate, polyethyleneimine, polyacrylamide, UV-activatable reactive group, peptidoglycan, or chitosan derivative, or a combination thereof.
  • the anchor region binds to a support material after a short period of UV irradiation.
  • the chemical entity is printed on or in a support material such as filter paper or a woven or non-woven material that is capable of being wet by a wound fluid and which displays capillary action.
  • the reporting entity or chemical entity is chemically bonded onto or into a support material such as filter paper or a woven or non-woven material that is capable of being wet by a wound fluid and which displays capillary action that is similar in all dimensions.
  • the chemical entity is ionically bound onto or into a support material such as filter paper or a woven or non-woven material that is capable of being wet by a wound fluid and which displays capillary action.
  • the chemical entity is covalently bound onto or into a support material such as filter paper or a woven or non-woven material that is capable of being wet by a wound fluid and which displays capillary action.
  • Support material includes, but is not limited to, cellulose, polyamide, polyester, polyacrylate and other similar polymers that are useful as fibers.
  • the support material is cellulose.
  • the support material is polyamide.
  • the support material is polyester.
  • the support material is polyacrylate.
  • the pH of a wound can influence many factors of wound healing, such as angiogenesis, protease activity, oxygen release, and bacterial toxicity.
  • Chronic nonhealing wounds may have an elevated alkaline environment. As the wound progresses towards healing, the pH of the wound moves to neutral and then becomes acidic. Monitoring of the pH of the wound may provide a method to assess the condition of the wound (e.g., infection or no infection) and aid in determining a wound’s response to treatment.
  • the chemical entity for the detection of infection in a wound comprises an indicator region comprising a pH-sensitive moiety that presents a visible color change.
  • the pH-sensitive moiety is selected from the group consisting of bromothymol blue, phenol red, bromophenol red, chlorophenol red, thymol blue, bromocresol green, bromocresol purple; nitrazine yellow; and sulfophthalein dyes or a combination thereof.
  • compositions are Compositions:
  • Embodiments described herein further relate to compositions containing the compounds of Formula I. Such compositions may be prepared using conventional methods.
  • the resulting stock composition of compounds of Formula I may be further modified into desired form, e.g., gels, balms, lotions, cream, paste, ointments, etc. using conventional methods, e.g., using carriers, gelling agents, emollients, surfactants, humectants, viscosity enhancers, emulsifiers, etc. See, e.g., WO 2013/004953.
  • Carriers for use in the composition may include, but are not limited to, water, glycerin, diglycerin, glycerin derivatives, glycols, glycol derivatives, sugars, ethoxylated and/or propoxylated esters and ethers, urea, sodium PCA, alcohols, ethanol, isopropyl alcohol, and combinations thereof.
  • the carrier is propylene glycol.
  • the composition contains a carrier in an amount from about 1% by weight of the composition to about 99.9% by weight of the composition, more typically from about 2% by weight of the composition to about 95% by weight of the composition, and more typically from about 5% by weight of the composition to about 90% by weight of the composition.
  • Thermo-reversible gelling agents are defined as ingredients that are soluble, partially soluble, or miscible in a hydrophilic carrier at elevated temperatures, such as 50° C., wherein the agents have the ability to thicken the carrier when cooled to 25° C., but will be less viscous at 50° C. when application to a substrate is necessary.
  • Suitable hydrophilic carriers include water, glycols, e.g., propylene glycol.
  • Thermo-reversible gelling agents for use in the composition may include salts of fatty acids such as sodium stearate, sodium palmitate, potassium stearate. These salts can be added to the composition or can be created in-situ by addition of the fatty acid and neutralizing with appropriate base.
  • compositions are to provide stearic acid and sodium hydroxide to produce sodium stearate.
  • Other common hermos-reversible gelling agents could include, e.g., polyethylene glycols and derivatives such as PEG-20, PEG-150 distearate, PEG-150 pentaerythrityl tetrastearate, disteareth-75 IPDI, disteareth-100 IPDI, fatty alcohols, e.g., cetyl alcohol, fatty acids such as stearic acid, hydroxystearic acid and its derivatives, and combinations thereof.
  • the composition can contain various other ingredients and components.
  • other ingredients that may be included within the composition are emollients, sterols or sterol derivatives, natural and synthetic fats or oils, viscosity enhancers, rheology modifiers, polyols, surfactants, alcohols, esters, silicones, clays, starch, cellulose, particulates, moisturizers, film formers, slip modifiers, surface modifiers, skin protectants, humectants, sunscreens, and the like.
  • Embodiments described herein further relate to pharmaceutical compositions and/or preparations comprising one or more of the aforementioned compounds of Formula I and a carrier.
  • pharmaceutically acceptable is employed herein to refer to those compounds, salts, compositions, dosage forms, etc., which are—within the scope of sound medical judgment—suitable for use in contact with the tissues of human beings and/or other mammals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • “pharmaceutically acceptable” means approved by a regulatory agency of the federal or a state government, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals (e.g., animals), and more particularly, in humans.
  • compositions may be prepared by any suitable means known in the art.
  • suitable means known in the art.
  • examples of such compositions include those adapted for: (a) topical application, e.g., articles (e.g., gauzes, pads, swabs, dressings), creams, ointments, gels, lotions, etc.; (b) parenteral administration, e.g., subcutaneous, intramuscular or intravenous injection as a sterile solution or suspension; (c) oral administration, external application (e.g. drenches including aqueous and non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pellets for admixture with feedstuffs, pastes for application to the tongue, etc.
  • the pharmaceutical compositions may comprise one or more antibiotic agents.
  • antibiotic or “antimicrobial agent” refers to a substance that inhibits the growth of or destroys microorganisms.
  • the antibiotic is useful in curbing the virulence of an infectious agent and/or treating an infectious disease.
  • Antibiotic also refers to semi-synthetic substances wherein a natural form produced by a microorganism, e.g., yeast or fungus is structurally modified.
  • the antibiotic is selected from the group consisting of ⁇ -lactams (including, ⁇ -lactamase inhibitors and cephalosporins), fluoroquinolones, aminoglycosides, tetracyclines and/or glycylcyclines and/or polymyxins.
  • ⁇ -lactams including, ⁇ -lactamase inhibitors and cephalosporins
  • fluoroquinolones aminoglycosides
  • tetracyclines and/or glycylcyclines and/or polymyxins Any combination of antimicrobial agents may also be employed, e.g., at least one ⁇ -lactam and at least one fluoroquinolone; at least one aminoglycoside and one cephalosporin; at least one ⁇ -lactam and one ⁇ -lactamase inhibitor, optionally together with an aminoglycoside, etc.
  • ⁇ -lactam includes natural and semi-synthetic penicillins and penicillin derivatives, e.g., benzathine penicillin, benzylpenicillin (penicillin G), phenoxymethylpenicillin (penicillin V), procaine penicillin and oxacillin; methicillin, dicloxacillin and flucloxacillin; temocillin; amoxicillin and ampicillin; azlocillin, carbenicillin, ticarcillin, mezlocillin and piperacillin; biapenem, doripenem, ertapenem, imipenem, meropenem, panipenem and PZ-601 ; cephalexin, cephalothin, cefazolin, cefaclor, cefuroxime, cefamandole, cefotetan, cefoxitin, cefotaxime, and cefpodoxime; cefepime and cefpirome; cefadrox
  • Fluoroquinolones include, ciprofloxacin, garenoxacin, gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin.
  • Aminoglycosides include, for e.g., kanamycin, amikacin, tobramycin, dibekacin, gentamicin, sisomicin, netilmicin, neomycin B, neomycin C, neomycin E (paromomycin) and streptomycin, including, synthetic derivatives clarithromycin and azithromycin.
  • Tetracyclines include naturally-occurring compounds (e.g., tetracycline, chlortetracycline, oxytetracycline, demeclocycline) or semisynthetic agents (e.g., lymecycline, meclocycline, methacycline, minocycline, roli tetracycline).
  • Glycylcyclines e.g., minocycline/tigecycline
  • Polymyxins include, e.g., polymyxin B and polymyxin E (colistin).
  • the compositions may contain an antibiotic at a concentration of 0.1 mg/mL, 0.5 mg/L, 1 mg/mL, 2 mg/mL, 3 mg/mL, 4 mg/mL, 5 mg/mL, 6 mg/mL, 7 mg/mL, 8 mg/mL, 9 mg/mL, 10 mg/mL, 11 mg/mL, 12 mg/mL, 13 mg/mL, 14 mg/mL, 15 mg/mL, 16 mg/mL, 17 mg mL, 18 mg/mL, 19 mg/mL, 20 mg/mL, 21 mg/mL, 22 mg/mL, 23 mg/mL, 24 mg/mL, 25 mg mL, 26 mg mL, 27 mg/mL, 28 mg/mL, 29 mg/mL, 30 mg/mL, 31 mg/mL, 32 mg/mL, 33 mg/mL, 34 mg mL, 35 mg/mL, 36 mg/mL, 37 mg/mL, 38 mg/mL, 10
  • wound dressings comprising wound dressing materials as described herein, e.g., compounds of Formula I.
  • the wound dressings consist essentially of the wound dressing materials as described herein, e.g., a compound of Formula I.
  • wound dressing disclosed herein are biocompatible, biodegradable, non-immunogenic and readily commercially available.
  • the compounds of Formula I are provided in the form of particles, such as fiber particles or powder particles, optionally containing a medicament.
  • the materials preferably contain CMC fibers.
  • compositions may preferably comprise an intimate mixture of the dressing material and other compounds.
  • the intimate mixture comprises a mixed solution or dispersion of the dressing material and a suitable vehicle, such as a solvent, or a solid composition produced by removing solvent from such a solution or dispersion.
  • the dressing material makes up at least 5%, more preferably at least 10%, 20%, 30%, 50%, 75%, 90% or greater % by weight of the material.
  • the material consists essentially of the dressing material.
  • Other components of the material may include 0-25% by weight, for example from about 1 to about 20% by weight, of one or more other biocompatible polysaccharides, for example alginates such as sodium alginate or calcium alginate, starch derivatives such as sodium starch glycolate, cellulose derivatives such as methyl cellulose or carboxymethyl cellulose, or glycosaminoglycans such as hyaluronic acid or its salts, chondroitin sulfate or heparan sulfate.
  • the materials may also comprise up to about 25% by weight, for example from about 1 to about 20%) by weight, of one or more structural proteins selected from the group consisting of fibronectin, fibrin, laminin, elastin, collagen and mixtures thereof.
  • the protein comprises collagen, and more preferably it consists essentially of collagen.
  • the materials may also comprise up to about 20% by weight, preferably from about 2% to about 10% by weight of water.
  • the materials may also contain 0-40% by weight, for example from about 5 to about 25% by weight, of a plasticizer, preferably a polyhydric alcohol such as glycerol or sorbitol.
  • the materials may also comprise up to about 10% by weight, for example from about 0.01 to about 5% by weight, typically from about 0.1 to about 2% by weight of one or more therapeutic wound healing agents, such as non-steroidal anti-inflammatory drugs (e.g., acetaminophen), steroids, local anesthetics, antimicrobial agents, or growth factors (e.g., fibroblast growth factor or platelet derived growth factor).
  • therapeutic wound healing agents such as non-steroidal anti-inflammatory drugs (e.g., acetaminophen), steroids, local anesthetics, antimicrobial agents, or growth factors (e.g., fibroblast growth factor or platelet derived growth factor).
  • the antimicrobial agent may, for example, comprise an antiseptic, an antibiotic, or mixtures thereof.
  • Preferred antibiotics include tetracycline, penicillins, terramycins, erythromycin, bacitracin, neomycin, polymycin B, mupirocin, clindamycin and mixtures thereof.
  • Preferred antiseptics include silver, including colloidal silver, silver salts including salts of one or more of the anionic polymers making up the material, silver sulfadiazine, chlorhexidine, povidone iodine, triclosan, sucralfate, quaternary ammonium salts and mixtures thereof.
  • the weight ratio of the wound dressing material to other auxiliary agents and materials is from about 1 :99 to about 99: 1. More preferably, the weight ratio is in the range about 1 :9 to about 9: 1, more preferably it is in the range about 4: 1 to about 1 :4, still more preferably in the range about 2: 1 to about 1 :2.
  • the material may be in any convenient form, such as a powder, microspheres, flakes, a mat or a film.
  • the material is in the form of a semisolid or gel ointment for topical application.
  • the material is in the form of a freeze-dried or solvent-dried bioabsorbable sponge for application to a chronic wound.
  • the average pore size of the sponge is in the region of 10-500 ⁇ m, more preferably about 100-300 ⁇ m.
  • a suitable sponge has been made by freeze-drying or solvent drying an aqueous dispersion comprising compounds of Formula I, together with suitable therapeutic agents.
  • the material is in the form of a flexible film, which may be continuous or interrupted (e.g. perforated).
  • the flexible film preferably comprises a plasticizer to render it flexible, such as glycerol.
  • both gel forming polymers e.g., cellulose derivatives
  • having a range of controllable properties means that the properties of the compositions the disclosed technology can be controlled to an exceptional degree.
  • the rate of biological absorption, porosity and density of the materials can be controlled.
  • wound dressing materials in sheet form comprising an active layer of a composition comprising compounds of Formula I.
  • the active layer would normally be the wound contacting layer in use, but in some embodiments it could be separated from the wound by a liquid-permeable top sheet.
  • the area of the active layer is from about 1 cm 2 to about 400 cm 2 , particularly from about 4 cm 2 to about 100 cm 2 .
  • the wound dressing material further comprises a backing sheet extending over the active layer opposite to the wound facing side of the active layer.
  • the backing sheet is larger than the active layer such that a marginal region of width 1 mm to 50 mm, preferably 5 mm to 20 mm extends around the active layer to form a so-called island dressing.
  • the backing sheet is preferably coated with a pressure sensitive medical grade adhesive in at least its marginal region.
  • the back sheet is substantially liquid-impermeable.
  • the backing sheet is semipermeable, e.g., the backing sheet is preferably permeable to water vapor, but not permeable to liquid water or wound exudate.
  • the backing sheet is also microorganism-impermeable.
  • Suitable continuous conformable backing sheets will preferably have a moisture vapor transmission rate (MVTR) of the backing sheet alone of 300 to 5000 g/m 2 /24 hrs, preferably 500 to 2000 g/m 2 /24 hrs at 37.5° C. at 100% to 10% relative humidity difference.
  • the backing sheet thickness is preferably in the range of 10 to 1000 micrometers, more preferably 100 to 500 micrometers.
  • Suitable polymers for forming the backing sheet include polyurethanes and poly alkoxyalkyl acrylates and methacrylates.
  • the backing sheet comprises a continuous layer of a high density blocked polyurethane foam that is predominantly closed-cell.
  • a suitable backing sheet material is a polyurethane film.
  • the adhesive layer should be moisture vapor transmitting and/or patterned to allow passage of water vapor.
  • the adhesive layer is preferably a continuous moisture vapor transmitting, pressure-sensitive adhesive layer of the type conventionally used for island-type wound dressings, for example, a pressure sensitive adhesive based on acrylate ester copolymers, polyvinyl ethyl ether and polyurethane. Polyurethane-based pressure sensitive adhesives may be selectively used.
  • the dressing may comprise further layers of a multilayer absorbent article may be built up between the active layer and the protective sheet.
  • these layers may comprise an apertured plastic film to provide support for the active layer in use, in which case the apertures in the film are preferably aligned in register with the apertures in the hydrogel layer.
  • the dressing may comprise an absorbent layer between the active layer and the protective sheet, especially if the dressing is for use on exuding wounds.
  • the optional absorbent layer may be any of the layers conventionally used for absorbing wound fluids, serum or blood in the wound healing art, including gauzes, nonwoven fabrics, superabsorbents, hydrogels and mixtures thereof.
  • the absorbent layer comprises a layer of absorbent foam, such as an open celled hydrophilic polyurethane foam.
  • the absorbent layer may be a nonwoven fibrous web, for example a carded web of viscose staple fibers.
  • the wound dressing may be protected by a removable cover sheet.
  • the cover sheet is normally formed from flexible thermoplastic material. Suitable materials include polyesters and polyolefins.
  • the adhesive-facing surface of the cover sheet is a release surface. That is to say, a surface that is only weakly adherent to the active layer and the adhesive on the backing sheet to assist peeling of the hydrogel layer from the cover sheet.
  • the cover sheet may be formed from a non-adherent plastic such as a fluoropolymer, or it may be provided with a release coating such as a silicone or fluoropolymer release coating.
  • the wound dressing is sterile and packaged in a microorganism-impermeable container.
  • kits comprising, in one or separate compartments, the compounds of Formula I, optionally together with an excipient, carrier or oil.
  • the kits may further comprise additional ingredients, e.g., gelling agents, emollients, surfactants, humectants, viscosity enhancers, emulsifiers, etc., in one or more compartments.
  • additional ingredients e.g., gelling agents, emollients, surfactants, humectants, viscosity enhancers, emulsifiers, etc.
  • the kits may optionally comprise instructions for formulating an article for diagnosing, detecting or treating wounds, e.g., chronic or infected wounds.
  • the kits may also comprise instructions for using the components, either individually or together, in the treatment of wounds.
  • kits comprising a package and at least one absorbent article (described above) comprising the aforementioned compositions.
  • the kits may comprise the individual components separately, optionally together with secondary information, useable in or with the package.
  • the wound is a chronic wound, for example a wound selected from the group consisting of venous ulcers, decubitis ulcers and diabetic ulcers.
  • Embodiments of the disclosed technology further provide for surfaces comprising the aforementioned compounds of Formula I, wherein the reporter or peptide is oriented to permit binding to a partner, e.g., an enzyme.
  • a partner e.g., an enzyme.
  • the surface is a surface of a solid support. Numerous and varied solid supports are known to those in the art.
  • Useful solid supports include natural polymeric carbohydrates and their synthetically modified, cross-linked or substituted derivatives, such as agar, agarose, cross-linked alginic acid, substituted and cross-linked guar gums, cellulose esters, especially with nitric acid and carboxylic acids, mixed cellulose esters, and cellulose ethers; natural polymers containing nitrogen, such as proteins and derivatives, including cross-linked or modified gelatins; natural hydrocarbon polymers, such as latex and rubber; synthetic polymers which may be prepared with suitably porous structures, such as vinyl polymers, including polyethylene, polypropylene, polystyrene, polyvinylchloride, polyvinylacetate and its partially hydrolyzed derivatives, polyacrylamides, polymethacrylates, copolymers and terpolymers of the above polycondensates, such as polyesters, polyamides, and other polymers, such as polyurethanes or polyepoxides; porous inorganic materials such as sulfates
  • the support is a well of an array plate, e.g., a microarray.
  • array plate e.g., a microarray.
  • Methods for constructing such arrays are known in the art, e.g., Cao et al., Appl Environ Microbiol , 77(23): 8219-8225, 201 1.
  • Each compound of Formula I (or the peptide indicators alone) may be spotted in triplicate to eliminate irregular data due to physical defects in the array.
  • Embodiments of the disclosed technology further provide for diagnostic systems comprising the aforementioned compositions and/or kits.
  • the various components of the diagnostic systems may be provided in a variety of forms.
  • the compounds of Formula I e.g., compounds containing peptide reporters
  • these lyophilized reagents may be pre-mixed before lyophilization so that when reconstituted they form a complete mixture with the proper ratio of each of the components ready for use in the assay.
  • the diagnostic systems of the disclosed technology may contain a reconstitution reagent for reconstituting the lyophilized reagents of the kit.
  • nucleic acids encoding the following peptides:
  • nucleic acids encoding the polypeptide sequences for ElaSubl CBM, CatGSubl CBM, ElaSubl CBM His, CatGSubl CBM His, ElaSub2_CBM, CatGSub2_CBM, ElaSub2_CBM His, CatGSub2_CBM His, ElaSubl PDM, CatGSubl_PDM, ElaSubl PDM His, CatGSubl PDM His, ElaSub2_PDM, CatGSub2 _PDM, ElaSub2_PDM His, CatGSub2_PDM or an enzyme-cleavable fragment thereof and/or an immunogenic fragment thereof.
  • nucleic acids encoding the polypeptide sequences set forth in Table 4 (for ElaSubl CBM, CatGSubl CBM, ElaSubl CBM His, CatGSubl CBM His, ElaSub2_CBM, CatGSub2_CBM, ElaSub2_CBM _His, CatGSub2_CBM_His) or an enzyme-cleavable fragment thereof and/or an immunogenic fragment thereof.
  • nucleic acid or “nucleic acid sequence,” as used herein, refer to an oligonucleotide, nucleotide, polynucleotide, or any fragment thereof, to DNA or RNA of genomic or synthetic origin which may be single- stranded or double- stranded and may represent the sense or the antisense strand, to peptide nucleic acid (PNA), or to any DNA-like or RNA-like material.
  • fragments refers to those nucleic acid sequences which are greater than about 10 nucleotides in length, and most preferably are at least about 40 nucleotides, at least about 100 nucleotides, or at least about 300 nucleotides in length.
  • Embodiments disclosed herein further relate to variants of the aforementioned polynucleotides.
  • nucleic acids which comprise, or alternatively consist of, a nucleotide sequence which is at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%, or greater % identity to, for example, the nucleic acids encoding the following peptides: X y AAPX y -Z , X y AAPX y -L-Z , X y AAP(V/F/A)X y -Z or X y AAP(V/F/A)X L-Z ; X N 4 N 3 N 2 Z 1 -Z or X N 4 N 3 N 2 Z 1 -L-Z , wherein X, N1, N2, N3, N4, L and Z are each, as described above.
  • nucleic acids which comprise, or alternatively consist of, a nucleotide sequence which is at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%, or greater % identity to, for example, the nucleotide coding sequence in ElaSubl CBM, CatGSub 1 CBM, ElaSubl CBM His, CatGSubl CBM His, ElaSub2_CBM, CatGSub2_CBM, ElaSub2_CBM His, CatGSub2_CBM His, ElaSub 1_PDM, CatGSub 1 PDM, ElaSubl PDM His, CatGSub 1 PDM His, ElaSub2 _PDM, CatGSub2 _PDM, ElaSub2_PDM His, CatGSub2_PDM His, or the complementary strand thereto, or the RNA equivalent thereof, or a complementary RNA equivalent thereof.
  • nucleotide sequence variants of aforementioned nucleic acids which comprise, or alternatively consist of, a nucleotide sequence which is at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%, or greater % identity to, for example, the nucleotide encoding the polypeptide sequences set forth in Table 4 (for ElaSub 1 CBM, CatGSubl CBM, ElaSub 1 CBM His, CatGSubl CBM His, ElaSub2_CBM, CatGSub2_CBM, ElaSub2_CBM_His, CatGSub2_CBM _His) , or the complementary strand thereto, or the RNA equivalent thereof, or a complementary RNA equivalent thereof.
  • Three-to-One Sequence Manipulation Suite which generates three potential nucleic acid sequences for each inputted polypeptide sequence
  • the Three-to-One software is available freely from bioinformatics(dot)org.
  • Percent identity refers to the percentage of sequence similarity found in a comparison of two or more amino acid or nucleic acid sequences. Percent identity can be determined electronically, e.g., by using the MEGALIGN program (LASERGENE software package, DNASTAR).
  • the MEGALIGN program can create alignments between two or more sequences according to different methods, e.g., the Clustal Method. (Higgins, D. G. and P. M. Sharp (1988) Gene 73 :237-244.)
  • the Clustal algorithm groups sequences into clusters by examining the distances between all pairs. The clusters are aligned pairwise and then in groups.
  • the percentage similarity between two amino acid sequences is calculated by dividing the length of sequence A, minus the number of gap residues in sequence A, minus the number of gap residues in sequence B, into the sum of the residue matches between sequence A and sequence B, times one hundred. Gaps of low or of no homology between the two amino acid sequences are not included in determining percentage similarity. Percent identity between nucleic acid sequences can also be calculated by the Clustal Method, or by other methods known in the art, such as the Jotun Hein Method. (See, e.g., Hein, J. (1990) Mehtods Enzymol. 183:626-645.) Identity between sequences can also be determined by other methods known in the art, e.g., by varying hybridization conditions.
  • hybridization refers to any process by which a strand of nucleic acid bonds with a complementary strand through base pairing.
  • hybridization under high stringency conditions could occur in about 50% formamide at about 37° C. to 42° C.
  • Hybridization could occur under reduced stringency conditions in about 35% to 25% formamide at about 30° C. to 35° C.
  • hybridization could occur under high stringency conditions at 42° C.
  • Hybridization could occur under reduced stringency conditions as described above, but in 35% formamide at a reduced temperature of 35° C.
  • the temperature range corresponding to a particular level of stringency can be further narrowed by calculating the purine to pyrimidine ratio of the nucleic acid of interest and adjusting the temperature accordingly. Variations on the above ranges and conditions are well known in the art.
  • hybridization complex refers to a complex formed between two nucleic acid sequences by virtue of the formation of hydrogen bonds between complementary bases.
  • a hybridization complex may be formed in solution or formed between one nucleic acid sequence present in solution and another nucleic acid sequence immobilized on a solid support (e.g., paper, membranes, filters, chips, pins or glass slides, or any other appropriate substrate to which cells or their nucleic acids have been fixed).
  • variants which are polynucleotide fragments of the aforementioned nucleic acids.
  • oligonucleotides e.g., PCR primers, which hybridize to one or more nucleic acids.
  • oligonucleotide refers to a nucleic acid sequence of at least about 6 nucleotides to 60 nucleotides, preferably about 15 to 30 nucleotides, and most preferably about 20 to 25 nucleotides, which can be used in PCR amplification or in a hybridization assay or microarray.
  • the term “oligonucleotide” is substantially equivalent to the terms “amplimers,” “primers,” “oligomers,” and “probes,” as these terms are commonly defined in the art.
  • PNA protein nucleic acid
  • PNA protein nucleic acid
  • PNA refers to an antisense molecule or anti-gene agent which comprises an oligonucleotide of at least about 5 nucleotides in length linked to a peptide backbone of amino acid residues ending in lysine. The terminal lysine confers solubility to the composition.
  • PNAs preferentially bind complementary single stranded DNA and RNA and stop transcript elongation, and may be pegylated to extend their lifespan in the cell. (See, e.g., Nielsen, P. E. et al. (1993) Anticancer Drug Des. 8:53-63.)
  • the vector comprises at least one protein encoding nucleic acid, e.g., nucleic acids encoding the polypeptide sequences for ElaSubl_CBM [SEQ ID NO: 20], CatGSub 1_CBM [SEQ ID NO: 201, ElaSubl _CBM His [SEQ ID NO: 211, CatGSubl __CBM His [SEQ ID NO: 221, ElaSub2_CBM [SEQ ID NO: 231, CatGSub2___CBM [SEQ ID NO: 241, ElaSub2_CBM His [SEQ ID NO: 251, CatGSub2__CBM His [SEQ ID NO: 261, ElaSubl _PDM, CatGSub 1_PDM, ElaSubl _PDM _His, CatGSubl PDM His, ElaSub2 _PDM, CatGSub2 _PDM, ElaSub2_PDM, ElaSub2_PDM
  • operably associated or “operably linked,” as used herein, refer to functionally related nucleic acid sequences.
  • a promoter is operably associated or operably linked with a coding sequence if the promoter controls the transcription of the encoded polypeptide. While operably associated or operably linked nucleic acid sequences can be contiguous and in reading frame, certain genetic elements, e.g., repressor genes, are not contiguously linked to the encoded polypeptide but still bind to operator sequences that control expression of the polypeptide.
  • Codon optimization for expression in a host cell e.g., bacteria such as E. coli or insect Hi5 cells
  • Codon Optimization Tool may be routinely performed using Codon Optimization Tool (CodonOpt), available freely from Integrated DNA Technologies, Inc., Coralville, Iowa.
  • the host cell is capable of recombinantly expressing the gene sequence contained in the vector under standard culture conditions to generate the polypeptide product, e.g., polypeptide sequences for ElaSub 1 CBM, CatGSubl CBM, ElaSub 1 CBM His, CatGSub 1 CBM His, ElaSub2_CBM, CatGSub2_CBM, ElaSub2_CBM His, CatGSub2_CBM His, ElaSub 1_PDM, CatGSub 1_PDM, ElaSub 1 PDM His, CatGSubl PDM His, ElaSub2_PDM, CatGSub2_PDM, ElaSub2_PDM His, CatGSub2_PDM or an enzyme-cleavable fragment thereof and/or an immunogenic fragment thereof.
  • the host cell is E. coli .
  • polypeptides comprising the following amino acid sequences: X y AAPX y -Z , X y AAPX y -L-Z , X y AAP(V/F/A)X y -Z or X y AAP(V F/A)X y -L-Z ; X y N 4 N 3 N 2 N 1 X y -Z or X y N 4 N 3 N 2 N 1 X y -L-Z , wherein X, N1, N2, N3, N4, L and Z are each, as described above.
  • polypeptide sequences set forth in Table 4 for ElaSubl CBM [SEQ ID NO: 111, CatGSub 1 CBM [SEQ ID NO: 121, ElaSub l_CBM_His [SEQ ID NO: 131, CatGSub l CBM His [SEQ ID NO: 14], ElaSub2_CBM [SEQ ID NO: 151] CatGSub2_CBM [SEQ ID NO: 161, ElaSub2_CBM His [SEQ ID NO: 171, CatGSub2_CBM_His [SEQ ID NO: 181] or an enzyme- cleavable fragment thereof and/or an immunogenic fragment thereof.
  • variants of aforementioned polypeptides which comprise, or alternatively consist of, an amino acid sequence which is at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%, or greater % identity to, for example, the following polypeptide sequences: X y AAPX y -Z , X y AAPX y -L-Z , X y AAP(V/F/A)X y -Z or X y AAP(V F/A)X y -L-Z ; X y N 4 N 3 N 2 N 1 X y -Z or X y N 4 N 3 N 2 N 1 X y -L-Z , wherein X, N1, N2, N3, N4, L and Z are each, as described above.
  • variant polypeptides which comprise, or alternatively consist of, an amino acid sequence which is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%o, 99%, or greater % identity to, for example, the polypeptide sequences for ElaSub 1 CBM, CatGSub 1 CBM, ElaSub 1 CBM His, CatGSub 1 CBM His, ElaSub2 CBM, CatGSub2_CBM, ElaSub2_CBM His, CatGSub2_CBM His, ElaSub 1 PDM, CatGSub 1 PDM, ElaSub 1 PDM His, CatGSub 1 PDM His, ElaSub2 _PDM, CatGSub2 _PDM, ElaSub2 _PDM His, CatGSub2_PDM or an enzyme-cleavable fragment thereof.
  • the fragment comprises a minimal structural motif for the enzyme recognition site (S) or enzyme-reactive site (R) for the hydrolase enzymes described herein, e.g., lysozyme, elastase, cathepsin G, MAO, or a combination thereof.
  • the fragment peptides are immunogenic molecules that can be recognized by antibodies or antigen-binding domains thereof.
  • homologs to the aforementioned peptides and polynucleotides.
  • a partially complementary sequence that at least partially inhibits an identical sequence from hybridizing to a target nucleic acid is referred to as “substantially homologous.” The inhibition of hybridization of the completely complementary sequence to the target sequence may be examined using a hybridization assay (Southern or northern blot, solution hybridization, and the like) under conditions of reduced stringency.
  • a substantially homologous sequence or hybridization probe will compete for and inhibit the binding of a completely homologous sequence to the target sequence under conditions of reduced stringency. This is not to say that conditions of reduced stringency are such that nonspecific binding is permitted, as reduced stringency conditions require that the binding of two sequences to one another be a specific (i .e., a selective) interaction.
  • the absence of non-specific binding may be tested by the use of a second target sequence which lacks even a partial degree of complementarity (e.g., less than about 30% homology or identity). In the absence of nonspecific binding, the substantially homologous sequence or probe will not hybridize to the second non-complementary target sequence.
  • variant peptides comprising a mutation in the core polypeptide sequence for ElaSub 1 CBM, CatGSub 1 CBM, ElaSubl CBM His, CatGSub 1_CBM His, ElaSub2_CBM, CatGSub2_CBM, ElaSub2_CBM His, CatGSub2_CBM His, ElaSub 1 PDM, CatGSub 1 PDM, ElaSubl PDM His, CatGSub1 PDM His, ElaSub2 PDM, CatGSub2 PDM, ElaSub2 PDM His, CatGSub2 PDM or an enzyme-cleavable fragment thereof.
  • the mutation is a substitution, deletion, addition of 1-3 amino acids.
  • the mutation does not change the enzyme recognition sites in the mutant peptides so formed. If the mutation results in a change in the composition of the recognition site or cleavage site, then it is contemplated that the mutation is due to a conserved amino acid substitution,
  • substitution refers to changes in an amino acid or nucleotide sequence resulting in the addition of one or more amino acid residues or nucleotides, respectively, to the sequence found in the naturally occurring molecule.
  • substitution refers to the replacement of one or more amino acids or nucleotides by different amino acids or nucleotides, respectively.
  • Embodiments disclosed herein further include antibodies which bind specifically to one or more of the aforementioned immunogenic peptides.
  • the antibodies bind to polypeptides comprising the following amino acid sequences: X y AAPX y -Z , X y AAPX y -L-Z , X y AAP(V/F/A)X y -Z or X y AAP(V F/A)X y -L-Z ; X y N 4 N 3 N 2 N 1 X y -Z or X y N 4 N 3 N 2 N 1 X y -L-Z , wherein X, N1, N2, N3, N4, L and Z are each, as described above.
  • the antibodies bind to fragment of these polypeptides.
  • Antigen-binding fragments of such antibodies e.g., F(ab) domain, F(ab) 2 domains, scFv domains, including synthetically generated antibodies (using, e.g., phase display technology).
  • the antibodies bind to polypeptide sequences for ElaSub1_CBM, CatGSub1_CBM, ElaSub1_CBM His, CatGSub1_CBM His, ElaSub2_CBM, CatGSub2_CBM, ElaSub2_CBM His, CatGSub2_CBM His, ElaSub1_PDM, CatGSub1_PDM, ElaSub1_PDM His, CatGSub1_PDM His, ElaSub2_PDM, CatGSub2_PDM, ElaSub2_PDM His, CatGSub2_PDM or an enzyme-cleavable fragment thereof and/or an immunogenic fragment thereof.
  • Antigen-binding fragments of such antibodies e.g., F(ab) domain, F(ab) 2 domains, scFv domains, including synthetically generated antibodies (using, e.g., phase display technology).
  • nucleic acids e.g., nucleic acids, proteins, peptides, and/or antibody molecules, including, conjugates thereof.
  • substantially purified refers to nucleic acids, amino acids or antibodies that are removed from their natural environment and are isolated or separated, and are at least about 60% free, preferably about 75% free, and most preferably about 90% free from other components with which they are naturally associated.
  • the biomolecules may be altered by combining with various components of the chemical entities, e.g., anchor region and/or indicator region, such that their form and/or functionality is significantly changed compared to any natural counterparts.
  • Embodiments provided herein further relate to methods of making compounds of Formula I, including precursors thereof.
  • precursor includes any compound which is employed as a reactant to generate an intermediary or a final product.
  • a method of making a compound of Formula I comprising the structure A-I, wherein, A is an anchor as described above and I is an indicator as described above, comprising, conjugating the anchor with the indicator molecule, e.g., via covalent bond.
  • the anchor or the indicator may comprise a recognition site (S) or a reaction/labile site (R) for a wound-specific marker, e.g., a wound-specific enzyme such as a hydrolase, and more specifically a protease or glycosidase, as described before.
  • the substrate for the wound-specific marker comprises, for example, a hydrolysable substrate, e.g., an amino acid, a sugar, a peptide, a polysaccharide, a nucleic acid, a lipid, or a combination thereof.
  • a hydrolysable substrate e.g., an amino acid, a sugar, a peptide, a polysaccharide, a nucleic acid, a lipid, or a combination thereof.
  • the anchor is conjugated to the reporter molecule via a peptide linkage, a glycosidic linkage, an amide linkage, an ester linkage, an ether linkage, an anhydride linkage or a similar linkage.
  • a “peptide bond” is formed by the condensation reaction between two amino acids, wherein the acid moiety of one reacts with the amino moiety of the other to produce a peptide bond (—CO—NH—) between the two amino acids.
  • the peptide bond is cleaved with a wound-specific protease, e.g., elastase, cathepsin G or MAO, or a combination thereof.
  • a “glycosidic bond” is formed between the hemiacetal or hemiketal group of a saccharide (or a molecule derived from a saccharide) and the hydroxyl group of some compound such as an alcohol.
  • the peptide bond is cleaved with a wound-specific glycosidase, e.g., lysozyme.
  • a method of making a compound of Formula I comprising the structure A-I, wherein, A and I are each, as described previously.
  • the A is conjugated to the I via a glycosidic linkage.
  • the A is conjugated to the I via a hydrophilic or hydrophobic linkage.
  • the compound of Formula I having the structure A-I is synthesized by first conjugating the anchor region A with the indicator region I to generate the compound of Formula I.
  • the indicator is first synthesized via genetic recombinant technology, e.g., expressing a nucleic acid encoding the indicator region in a suitable host cell, and combining the indicator with the anchor region.
  • the indicator region is designed to contain nucleic acid sequences which bind to the anchor region, e.g., hydrophilically or hydrophobically.
  • hydrophilic interaction comprises use of an anchor containing polar groups, e.g., partially deacetylated (e.g., DA of ⁇ 30%) chitosan, cellulose or carboxym ethyl cellulose (or a derivative thereof), which interacts with a hydrophilic carbohydrate binding module (CBM) from Cellobiohydrolase I ⁇ Trichoderma reesei).
  • an anchor containing polar groups e.g., partially deacetylated (e.g., DA of ⁇ 30%) chitosan, cellulose or carboxym ethyl cellulose (or a derivative thereof)
  • CBM hydrophilic carbohydrate binding module
  • hydrophobic interaction comprises use of an anchor containing non-polar groups, e.g., polyethylene terephthalate (or a derivative thereof), which interacts with a or the hydrophobic binding module from Alcaligenes faecalis Polyhydroxyalkanoate depolym erase (PDB).
  • an anchor containing non-polar groups e.g., polyethylene terephthalate (or a derivative thereof)
  • PDB Polyhydroxyalkanoate depolym erase
  • peptide indicators e.g., polypeptides comprising the following amino acid sequences: X y AAPX y -Z , X y AAPX y -L-Z , X y AAP(V/F/A)X y -Z or X y AAP(V/F/A)X y -L-Z ; X y N 4 N 3 N 2 N 1 X y -Z or X y N 4 N 3 N 2 N 1 X y -L-Z , wherein X, N1, N2, N3, N4, Land Z are each, as described above, (including variant polypeptides) may be synthesized via host-cell expression systems.
  • Such a method may comprise, for example, generating a construct encoding one or more of the aforementioned polypeptides or variants, placing said construct in a suitable vector, e.g., plasmid vector or baculovirus vector, transfecting a host cell, e.g., E coli or insect Hi5 cells, with the vector; culturing the host cells under suitable conditions to allow expression of said vector; and optionally purifying the expressed polypeptide from the culture.
  • a suitable vector e.g., plasmid vector or baculovirus vector
  • peptide indicators e.g., polypeptides comprising the following amino acid sequences: X y AAPX y -Z , X y AAPX y -L-Z , X y AAP(V/F/A)X y -Z or X y AAP(V/F/A)X y -L-Z ; X y N 4 N 3 N 2 N 1 X y -Z or X y N 4 N 3 N 2 N 1 X y -L-Z , wherein X, N1, N2, N3, N4, Land Z are each, as described above (including variant polypeptides) may be synthesized using solid-phase peptide synthesis (see, Merrifield et al., J. Am. Chem. Soc. 85 (14): 2149-2154).
  • the compound of Formula I having the structure A-I may be synthesized in a single reaction chamber or multiple reaction chambers.
  • the compositions, dressing materials, articles, kits and systems described herein are useful in diagnosing or treating wounds, particularly chronic or infected wounds.
  • any type of wound may be diagnosed and/or treated, the embodiments are particularly suitable for diagnosing and treating wounds that exude wound fluid.
  • the wound may be a chronic or acute wound.
  • Representative examples of chronic wounds include, e.g., venous ulcers, pressure sores, decubitis ulcers, diabetic ulcers and chronic ulcers of unknown aetiology.
  • Representative examples of acute wounds include, e.g., acute traumatic laceration, perhaps resulting from an intentional operative incision.
  • a wound fluid refers to any wound exudate or other fluid (suitably substantially not including blood) that is present at the surface of the wound, or that is removed from the wound surface by aspiration, absorption or washing.
  • the determining, measuring or quantifying is suitably carried out on wound fluid that has been removed from the body of the patient, but can also be performed on wound fluid in situ.
  • wound fluid does not normally refer to blood or tissue plasma remote from the wound site.
  • the wound fluid is mammalian wound fluid, suitably human wound fluid.
  • the diagnostic method comprises contacting a wound with at least one composition comprising a compound of Formula I or Formula II, a dressing material comprising such compounds, article comprising such materials or compounds, kits comprising such materials or compounds, or a system comprising such materials or compounds described herein; and measuring a parameter associated with the wound.
  • the parameter being measured is a level or activity of a wound-specific hydrolase.
  • the parameter being measured is the activity of the hydrolase.
  • the measurement may either be made in situ or ex situ.
  • in situ refers to processes, events, objects, or components that are present or take place within the context of the system or device, including, the surrounding environment, for example, the biological material with which the composition, article, system or device is in contact with.
  • an in situ reaction may refer to the reaction of the various components present in the device (e.g., compound of Formula I or Formula II), including, components provided by the human skin tissue (e.g., wound exudate containing the enzyme).
  • ex situ refers to outside of the environment.
  • the measurement is performed ex situ, e.g., removing the fluid from the wound for analysis in the apparatus or device of the disclosed technology.
  • the measurement is made in situ.
  • the method comprising determining a level of a reporter, e.g., a product of a substrate acted upon by a wound-specific enzyme. More specifically, the method comprises determining a level of a hydrolase enzyme product.
  • determining includes measuring a numerical value of the activity or level of said hydrolase; establishing if the activity or level falls above or below a predetermined range; and/or comparing the numerical value of activity or level with a control standard.
  • the control standard may comprise determining a level or activity of the hydrolase in a biopsy material obtained from an unwounded site or from a healthy subject.
  • the term “determining” comprises measuring the parameter (e.g., activity or level) of at least one wound specific protease is selected from the group consisting of MMP-1 (collagenase), MMP-2 (gelatinase A), MMP-3 (stomelysin 1), MMP-8 (neutrophil collagenase), MMP-9 (gelatinase B), human neutrophil elastase (HNE), cathepsin G, urokinase-type plasminogen activator (uPA), and lysozyme, or a combination thereof; establishing if said parameter exceeds a first predetermined threshold; and/or comparing the numerical value of parameter with a control standard.
  • MMP-1 collagenase
  • MMP-2 gelatinase A
  • MMP-3 stomelysin 1
  • MMP-8 neutral collagenase
  • MMP-9 gelatinase B
  • HNE human neutrophil elastase
  • cathepsin G cathe
  • the control standard may comprise determining a parameter of the protease in a biopsy material obtained from an unwounded site or from a healthy subject.
  • the term “determining” comprises establishing whether a weighted average (weighted sum) of the parameters associated with a plurality of the aforementioned proteases exceeds a predetermined threshold value for said weighted average.
  • the parameter is activity level of the analyte (e.g. a protease) in a wound fluid.
  • the activity of an individual analyte is expressed in terms units/mL.
  • the parameter is the level of the analyte (e.g., protease) in a wound fluid.
  • the term amount is also indicative of the activity of a particular analyte.
  • the term “combined amount” or “combined activity” refers to a single numerical value that results from the application of a mathematical function to a plurality of values, for example those amounts obtained for a number of individual analytes.
  • the term “combined amount” or “combined activity” may refer to the sum or product of a group of individual values.
  • the term “combined amount” or “combined activity” relates to the sum of a group of individual values.
  • the amount of elastase refers to elastase-like activity (e.g., U/mL) and the amount of metalloproteinase (MMP) refers to total concentration of the respective analyte (e.g., in ng/mL).
  • MMP metalloproteinase
  • the term “quantifying” refers to measuring an absolute numerical quantity of a particular analyte(s) or substrate(s) in a sample, within the margins of experimental error.
  • markers refers to any chemical entity that is identified or determined using the apparatus, devices, kits or methods defined herein.
  • the markers or analytes determined or identified by the apparatus, devices, kits or methods of the disclosed technology are cleaved products of the aforementioned enzymes.
  • the term “predetermined range” refers to a data range or profile that the skilled person would understand is indicative of a particular sub-class of patient.
  • the predetermined range may be a data range or profile that is typical of a wound that would respond well to a particular wound treatment, such as antibiotic therapy.
  • the predetermined range may suitably refer to a data range that is typical of a wound that would not respond well to a particular wound treatment, such as antibiotic therapy.
  • the term “predetermined threshold” refers to a minimum level that the skilled person would determine is indicative of a non-healing wound based on statistical analysis of levels determined for known healing and non-healing wounds, for example as explained further above.
  • the threshold should be set at an appropriate level so that non-healing wounds with high protease activity are correctly identified. Increasing the threshold will increase the chance of only non-healing wounds being over the threshold. However, if the threshold is too high, wounds that are non-healing due to a high level of proteases would not be identified and clinically this would mean they would not receive the required protease modulating treatment.
  • control standard refers to a data set or profile that can be used as a reference or comparison in order to define or normalize another data point or set of data.
  • control or “control standard” may be data set or profile that is indicative of a particular sub-class of patient.
  • control standard may be a data set or profile indicative of healing or non-healing wound status.
  • control or “control standard” can be a data set or profile that can be used as a comparative tool to allow a skilled person to determine whether a wound is likely to be responsive or non-responsive to a wound treatment, such as antibiotic therapy.
  • control standard is a data set or profile indicative of a patient that does not respond well to wound treatment.
  • control standard is a data set or profile indicative of a patient that responds well to wound treatment.
  • Patients that tend to respond well to wound treatment as disclosed herein exhibit lower combined amount or activity of hydrolases than patients that tend not to respond well to the treatment. For example, patients that tend to respond well to wound treatment as disclosed herein exhibit lower combined amounts of at least one wound-specific hydrolase.
  • the threshold human neutrophil elastase activity is about 5 U/mL to about 30 U/mL, including all values in between, e.g., about 6 U/mL, about 7 U/mL, about 8 U/mL, about 9 U/mL, about 10 U/mL, about 11 U/mL, about 12 U/mL, about 13 U/mL, about 14 U/mL, about 15 U/mL, about 16 U/mL, about 17 U/mL, about 18 U/mL, about 19 U/mL, about 20 U/mL, about 21 U/mL, about 22 U/mL, about 23 U/mL, about 24 U/mL, about 25 U/mL, or more, indicate chronic wound infection.
  • the threshold human neutrophil elastase activity levels of at least 9.6 indicate chronic wound infection. In some embodiments, human neutrophil elastase activity levels of at least 22.9 U/mL indicate chronic wound infection.
  • the threshold cathepsin G activity levels of about 10 U/mL to about 100 U/mL including all values in between, e.g., about 15 U/mL, about 20 U/mL, about 25 U/mL, about 30 U/mL, about 35 U/mL, about 40 U/mL, about 45 U/mL, about 50 U/mL, about 55 U/mL, about 60 U/mL, about 65 U/mL, about 70 U/mL, about 75 U/mL, about 80 U/mL, about 85 U/mL, about 90 U/mL, about 95 U/mL, about 100 U/mL, about 1 10 U/mL, about 120 U/mL, or more, indicate chronic wound infection.
  • cathepsin G activity levels of at least 50 U/mL, at least 40 U/mL, at least 30 U/mL, at least 20 U/mL, at least 15 U/mL or at least 10 U/mL indicates chronic wound infection.
  • Embodiments disclosed herein further relate to treatment of chronic or infected wounds using the compositions, materials, articles, dressings, kits and/or systems described herein.
  • the therapeutic embodiment includes, contacting a composition, material, article, dressing, kit, system or devices of the disclosed technology with a subject in need thereof.
  • the method may include determination of whether the subject is responding to the treatment.
  • wounds are “responsive to treatment” or not.
  • the skilled person will readily be able to determine the levels of the proteases identified in the present claims that are predictive or indicative of a good response or poor response to wound treatment, particularly to treatment with wound dressings comprising oxidized cellulose.
  • responsive and responder(s) refer to wounds that are considered to respond well to wound treatment, particularly to treatment with a pharmacological agent, e.g., antibiotics.
  • non-responsive and non-responder(s) refers to wounds that are not considered to respond well to wound treatment, particularly to treatment with the pharmacological agent, e.g., antibiotics. For instance, patients who exhibit better than 50% wound closure after 4 weeks of wound treatment are considered to be responsive to said treatment.
  • a patient may be simultaneously diagnosed and treated with the compositions, articles, systems, or devices described herein.
  • the term “simultaneously” means performing the stated objectives, e.g., diagnosis and treatment, together.
  • a patient may be sequentially diagnosed and treated with the compositions, articles, systems, or devices described herein.
  • Embodiments described herein further enable a care giver or a patient to determine quickly and reliably whether a wound is likely to be non-healing, and to select an appropriate therapy based on this determination.
  • non-healing wounds may require the application of special wound dressings such as wound dressings comprising specific therapeutic agents, to promote healing.
  • embodiments described herein further provide methods of treatment of a wound, e.g., chronic or infected wounds, comprising determining whether a wound is healing or non-healing, followed by applying a wound dressing comprising a therapeutic agent to the wound if it is non-healing.
  • Embodiments described herein provide methods and assays for diagnosis or detection of infected wounds.
  • the methods are suitable for the detection of bacterial infectious agents.
  • the wounds are infected with gram-negative bacteria.
  • Typical gram-negative bacteria include proteobacteria such as E. coli, Salmonella, Pseudomonas, and Helicobacter, and cyanobacteria .
  • the wounds are infected with gram-positive bacteria.
  • gram-positive bacteria is meant a bacterium or bacteria that contain(s) teichoic acid ⁇ e.g., lipoteichoic acid and/or wall teichoic acid), or a functionally equivalent glycopolymer ⁇ e.g., a rhamnopolysaccharide, teichuronic acid, arabinogalactan, lipomannan, and lipoarabinomannan) in its cell wall.
  • functionally equivalent glycopolymers are described in Weidenmaier et al, Nature , 6:276-287, 2008.
  • the bacteria include pathogenic bacteria that infect mammalian hosts ⁇ e.g. , bovine, murine, equine, primate, feline, canine, and human hosts).
  • pathogenic bacteria include, e.g., members of a bacterial species such as Bacteroides, Clostridium, Streptococcus, Staphylococcus, Pseudomonas, Haemophilus, Legionella, Mycobacterium, Escherichia, Salmonella, Shigella, Vibrio, or Listeria .
  • the infectious bacteria is selected from the group consisting of Clostridium difficile , Carbapenem-Resistant Enterobacteriaceae (CK- Klebsiella spp; CK- E. coli ), and Neisseria gonorrhoeae .
  • the infectious bacteria is selected from the group consisting of multi drug-resistant Acinetobacter , drug-resistant Campylobacter , extended spectrum ⁇ -Lactamase (ESBL)-producing enterobacteriaceae , vancomycin-resistant enterococcus , multidrug-resistant pseudomonas aeruginosa , drug-resistant non-typhoidal Salmonella , drug-resistant Salmonella enterica serovar Typhi , drug-resistant Shigella , methicillin-resistant Staphylococcus aureus (MRSA), drug-resistant Streptococcus pneumoniae , and drug-resistant Tuberculosis .
  • multi drug-resistant Acinetobacter drug-resistant Campylobacter
  • ESBL extended spectrum ⁇ -Lactamase
  • ESBL extended spectrum ⁇ -Lactamase
  • ESBL extended spectrum ⁇ -Lactamase
  • ESBL extended spectrum ⁇ -Lactamase
  • ESBL extended spectrum ⁇ -Lactamas
  • the infectious bacteria is selected from the group consisting of vancomycin-resistant Staphylococcus aureus , erythromycin-resistant Group A Streptococcus , clindamycin-Resistant Group B Streptococcus .
  • the chronic or infected wounds are found in host subjects.
  • the hosts are mammals, e.g., a rodent, a human, a livestock animal, a companion animal, or a non-domesticated or wild animal.
  • the subject may be a rodent, e.g. a mouse, a rat, a guinea pig, etc.
  • the subject may be a livestock animal.
  • suitable livestock animals may include pigs, cows, horses, goats, sheep, llamas and alpacas.
  • the subject may be a companion animal.
  • companion animals may include pets such as dogs, cats, rabbits, and birds.
  • the subject may be a zoo animal.
  • a “zoo animal” refers to an animal that may be found in a zoo. Such animals may include non-human primates, large cats, wolves, and bears.
  • the subject is a human.
  • kits for detecting levels of one or more enzymes in a mammalian wound comprising the steps of: (a) placing the wound dressing material described herein in contact with the mammalian wound; (b) visually comparing the wound dressing material in contact with the mammalian wound with one or more reference samples; and (c) obtaining a qualitative determination of the concentration of reporter molecules in the wound dressing material in contact with the mammalian wound.
  • the diagnosis and treatment is conducted in situ.
  • Embodiments described herein therefore allow diagnosis and treatment of wounds in an easy, non-invasive manner.
  • the diagnosis may be made in real time and the treatment may be applied to the infected wound or to the patient (systemically) and the progress of wound treatment be monitored over real-time, e.g., dissipation of the signal generated by the reporter molecule due to wound-healing.
  • a chemical entity comprises one or more components selected from the group consisting of: an anchor region, an enzyme-labile or enzyme-reactive region, and an indicator region.
  • the method compromises placing substrates for MPO, elastase, lysozyme, phospholipase, and catalase on a solid surface such that any reaction is visible to the eye.
  • the method serves to assess a variety of body fluids including wound, tear, vitreal, CSF, airway aspirates or sputum, synovial, blood, plasma, serum, urine, peritoneal, interstitial, subcutaneous, bile, intestinal or similar fluids, via contacting them with a material containing the substrates and assessing the change of the substrates thereafter.
  • Chitosan (10 g, from shrimp shells) was dissolved in 2% acetic acid solution (1 L). The solution was stirred overnight at room temperature and afterwards filtered using a nylon filter (0.45 ⁇ t). Subsequently the pH was adjusted to 8 by the addition of 4 M NaOH to precipitate chitosan. The obtained precipitate was isolated by centrifugation (10000 rpm, 10 min) and thoroughly washed with distilled water until the pH of the washing solution reached ⁇ 7. Afterwards the precipitate was washed with 90% ethanol, the remaining ethanol was allowed to evaporate and the chitosan was freeze-dried. The purified product was analyzed by FTIR (1560 cm ′1 , 1640 cm ′′1 ) and material with an approximate DA of 48% was used further
  • chitosan (example 1) was dissolved in 10% acetic acid solution to obtain a 1% chitosan solution. An equal volume of 96% Ethanol was added as well as acetic anhydride. The reaction was stirred for 1 h before the pH was adjusted to 7. The precipitate was isolated by centrifugation and freeze-dried. Subsequently, the obtained acetylated chitosan was several times washed with distilled water and again freeze-dried. The degree of N-acetylation (DA) was analyzed by ⁇ -NMR and FTIR (1560 cm ′′1 , 1640 cm ′′1 ) and found to be 40-60% as indicated in the graphic below. Chitosan derivatives with varying DA were produced, but only material with a DA of 48% was further used
  • a solution consisting of 2.5% (w/v) Na 2 SO 4 and 1% (w/v) Na 2 CO 3 in distilled water was added, and the mixture was incubated at 25° C. for 10 min. After a subsequent incubation step at 65° C., the solid was isolated by centrifugation (7800 rpm, 5 min). The precipitate was washed with distilled water until the washing solution remained colorless and subsequently freeze dried.
  • the dye content was determined measuring the unbound reactive black 5 after the reaction was completed. The dye was largely associated with the precipitate and high MW fraction. Degree of acylation was 48%.
  • chitosan (2.5 g; Example 1) was dissolved in acetate buffer (100 mM, pH 5) to obtain a 1% chitosan solution. Afterwards chitosanase from Streptomyces griseus (1 unit) was added and the reaction mixture was stirred for 5 d on a thermomixer (37° C., 150 rpm). The solution was concentrated in vacuo and non-oligomeric chitosan was precipitated using 1 volumetric equivalent of 96% ethanol. The supernatant was concentrated again and subsequently oligosaccharides were precipitated by the addition of 9 volumetric equivalents of acetone.
  • the oligosaccharides were isolated by centrifugation, several times washed with 50% acetone in water, and freeze-dried without prior washing.
  • the degree of polymerization was determined by TLC and SEC (TSK gel G5000 PWXL, Pullulan as standard), indicating a mean MW of 5360 associated to a degree of polymerization of ca. 24.
  • Mn Number molecular weight
  • PDI Polydispersity Index
  • DP Degree of polymerization
  • a chitooligosaccharide mixture (7 g) (example 4) was dissolved in distilled water (200 mL) before 96% ethanol (400 mL) was added. The solution was stirred for 5 min and acetic anhydride (4.12 mL, 1 molar equiv. calc. to free amines) was added. The mixture was stirred for further 2 h at room temperature before the pH was adjusted to 7 with a 10%) NaOH solution. The solvent was removed, and the remaining precipitate was freeze-dried. The degree of N-acetylation was analyzed by 1 H-NMR, FTIR (1560 cm -1 , 1640 cm -1 ) and dye content (photometrically, 626 nm). The degree of N-acetylation was found to be 48 %.
  • Lysozyme digestion of dyed chitosan derivatives The synthesized substrates were investigated in different media: potassium phosphate buffer (66 mM, pH 6.2) as well as artificial wound fluid containing 5000 U of lysozyme from hen egg white, and human wound fluid from infected wounds (see FIGS. 5 and 6 ).
  • Two milligrams of the lysozyme substrates was suspended in the respective test medium and incubated at 35° C.
  • the sample was briefly centrifuged, 200 ⁇ L of the supernatant was transferred to a 96-well plate and photometrically analyzed at the absorption maximum of the respective dye. After the analysis, the withdrawn sample was returned in the reaction vial and further incubated.
  • composition of the artificial wound fluid contained human serum albumin (2%), sodium chloride (0.36%), sodium bicarbonate, (0.05%), sodium citrate (0.02%), sodium lactate (0.1%), glucose (0.1%), calcium chloride dihydrate (0.01%), magnesium chloride (0.02%), and urea (0.01%).
  • Example 7 Synthesis of Indol/Chitooligomer Based Substrates for the Detection Of Wound Infection.
  • COSs chito oligosaccharides
  • DP degree of polymerization
  • Example 8 1-chloro,3-O,6-O-Diacetyl-4-O-[3-O,4-O,6-O-triacetyl-2- (acetylamino)-2-deoxy-P-D-glucopyranosyl]-2-(acetylamino)-2-deoxy- ⁇ -D-glucopyranoside (Compound 7)
  • Chitobiose octaacetate 2 (20 mg) was suspended in acetyl chloride and the solution was saturated with HCl gas and stirred for 30 h. Afterwards the solution was evaporated and used without further purification.
  • Example 9 1-(5-Bromo-4-chloro-N-acetyl-3-indolyl),3-0,6-0-Diacetyl-4-0-[3-0,4-O,6-O-triacetyl-2-(acetylamino)-2-deoxy- ⁇ -D-glucopyranosyl]-2-(acetylamino)-2-deoxy- ⁇ -D-glucopyranoside (Compound 13)
  • a 12 g MPLC column was used for the separation with a gradient of pure chloroform to 15 parts chloroform to one part ethanol over 10 column volumes. Then 5 column volumes 15 parts chloroform to one part ethanol were used isocratic. The final flushing step was 10 parts chloroform to one part ethanol for 5 column volumes.
  • GlcNAc 14 (100 mg) was dissolved in H 2 0 (1.8 mL) and triethylamine (0.6 mL) was added. The solution was chilled in an ice bath prior to the addition of 2-chloro-1, 3-dimethylimidazolinium chloride (DMC, 230 mg). The solution was stirred for 30 min. DMC and TEA were removed by MPLC (CI 8) using H 2 0 as eluent. The product fractions were pooled and concentrated in vacuo .
  • DMC 2-chloro-1, 3-dimethylimidazolinium chloride
  • N-Acetyl- ⁇ -D-glucosamine tetraacetate (391 mg, 1.00 mmol) was suspended in acetyl chloride (7 mL) while cooling with an ice bath. The mixture was degassed with argon for 5 min. Afterwards MeOH (1.00 mL) was added dropwise over a period of two hours. During the first 15 min of MeOH addition the reaction mixture was degassed with argon; then it was kept under argon atmosphere (stirred in ice bath all the time). After complete addition of the MeOHl the reaction mixture was stirred additional 10 min with cooling in an ice bath. Afterwards it was allowed to warm to RT and was stirred at RT overnight. The mixture was concentrated to dryness, taken up in DCM (10 mL), concentrated to dryness again, taken up in diisopropyl ether (15 mL) and concentrated to dryness once more to yield a yellow solid which was used without further purification.
  • Example 12 (jV-Acetyl-5-bromo-4-chloro-indol-3-yl) 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-D-glucopyranoside (12a) and (5-Bromo-4-chloro-indol-3-yl) 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-D-glucopyranoside (12b)
  • Example 19 The crude product of Example 19 was dissolved in acetyl chloride (1 mL) under argon atmosphere and cooled in an ice bath. MeOH (55 ⁇ L) was added dropwise within approximately 1 min. After complete addition the mixture was stirred in the ice bath for additional 10 min, then the solution was allowed to warm to RT; additional acetyl chloride (5 mL) was added. The mixture was stirred at RT overnight. Afterwards it was concentrated to dryness, taken up in dichloromethane (5 mL), concentrated to dryness again, suspended in diisopropyl ether and concentrated to dryness another time to yield 55 mg crude product. The crude product was used for the next step without further purification.
  • Example 20 Synthesis of Phenol/Chitosan/Laccases Based Substrates for The Detection of Wound Infection.
  • N-acetyl chitosan was dissolved in sodium acetate buffer (100 mM, pH 5.0) to obtain a 1% solution (w/v). 20 mL of this solution were mixed with 20 mL of a sinapic acid solution in ethanol (20 mM). EDC and NHS were added (1.3 g each) and the solution was stirred for 2 h. The reaction was stopped by adding NaOH (1 M) drop-wise, the resulting precipitate was washed with water until no phenol could be detected anymore in the washing solution. Afterwards the product was freeze dried.
  • N-acetyl chitosan was dissolved in sodium acetate buffer (100 mM, pH 5.0) and aminomethoxyphenol (dissolved in ethanol) was added to obtain a total concentration of 20 mM. 2.3 mL of this solution were mixed with 1.6 mL of dodecane and applied to a sonicator to produce an emulsion.
  • SA grafted N-acetyl chitosan (5 mg) was suspended in 500 potassium phosphate buffer (62 mM, pH 6.2) containing lysozyme (0.1 mg/mL). The solution was incubated for one hour. The reaction supernatant was incubated with laccase (1 U/mL) and an immediate color change was observed.
  • N-acetyl chitosan / aminomethoxyphenol nanoparticle emulsion 50 ⁇ L was mixed with 450 ⁇ L potassium phosphate buffer (62 mM, pH 6.2) containing lysozyme (0.1 mg/mL) and laccase (1 U/mL). The nanoparticles were destructed after 15 min (yielding a clear solution) developing strong colour.
  • Different reactive dyes can be used for the dying of peptidoglycan (Table 1).
  • reactive dyes containing a sulfonylethyl-hydrogensulphate-reactive-group such as reactive black 5, remazol brilliant blue, reactive violet 5 or reactive orange 16.
  • dyes containing a dichlortriazine reactive-group such as reactive blue 4, reactive red 120, reactive blue 2, reactive green 19 and reactive brown 10 can be used.
  • Dyes were evaluated by consideration of their degree of reaction with peptidoglycan and the speed with which the dye was released when the dyed peptidoglycan was incubated with lysozyme (see earlier section of Example 7 for dying and Example 6 for digestion assay).
  • Micrococcus lysodeicticus cell broth from an animal free fermentation was centrifuged at 4000 g and 4° C. for 15 min to gain a wet cell pellet.
  • the cell pellet (20 g) was washed twice with ddH20 (800 ml) to get rid of any remaining media components (constant centrifugation conditions).
  • the wet Micrococcus lysodeicticus cell pellet (20 g, we dry ration 4: 1, 5 g dry M. lysodeicticus cells) were suspended in 1 M HCl (80 g) and incubated for 1 h at 60° C. and 720 rpm. The sterilized and interrupted cells were then centrifuged at 4000 g and 4° C. for 15 min.
  • the peptidoglycan pellet was resuspended and washed with Na-Phosphate buffer (400 ml, 100 mM, pH 7.0) to adjust the pH of the suspension to a neutral pH and to get rid of cell components of the disruption process (constant centrifugation conditions).
  • Another washing step with 500 ml of ddH20 was carried out to get rid of disrupted cell components and buffer salts. The gained pellet after the last washing step was ready to use for the staining procedure.
  • Peptidoglycan 50 mg
  • reactive black 5 5 mg
  • Na2C03 10 mg
  • Na2S04 25 mg
  • ddH20 double-distilled water
  • the reaction mixture was incubated at 25° C. and 750 rpm for 10 min followed by a second incubation step at 65° C. and 750 rpm-shaking for another 30 min.
  • the dyed peptidoglycan was centrifuged at 10000 g for 10 min. The supernatant was collected, and the pellet was re-suspended in ddH20 and centrifuged again at 10000 g for 10 min. The washing procedure was repeated until the supernatant was clear. Different buffers or organic solvents like ethanol could be used for the washing procedure. The absorbance levels of all supernatants were measured at 597 nm. The supernatant was defined as clear, if the absorbance was below a value of 0.05. The amount of unbound dye in the supernatant was calculated using a calibration curve and the measured absorbance levels of the supernatants. Consequentially, the amount of peptidoglycan-bound dye was calculated. The dyed peptidoglycan was stored at 4-8° C. for a maximum of 2 wks or dried via lyophilization for a longer storage period.
  • Reactive black 5 200 mg
  • peptidoglycan 300 mg
  • ddH20 40 mL
  • the reaction solution was stirred at 50° C. for 30 min.
  • Na2S04 1 g
  • Na3P04 200 mg was added to the reaction solution, which was stirred again for 30 min at 50° C.
  • the dyed peptidoglycan was centrifuged at 10000 g for 10 min. The supernatant was collected, and the pellet was re-suspended in ddH20 and was again centrifuged at 10000 g for 10 min. The washing procedure was repeated until the supernatant was clear. Different buffers or organic solvents like ethanol could be used for the washing procedure. The absorbance levels of all supernatants were measured at 597 nm. The supernatant was defined as clear, if the absorbance was below a value of 0.05. The amount of unbound dye in the supernatant was calculated using a calibration curve and the measured absorbance levels of the supernatants. Consequentially, the amount of peptidoglycan-bound dye was calculated. The dyed peptidoglycan was stored at 4-8° C. where it appears to be stable or dried via lyophilisation.
  • Peptidoglycan (150 mg, dry weight) was suspended in ddH20 (20 ml) and heated to 50° C.
  • the reaction was started by the addition of reactive black 5 (7 different variants with different amounts of reactive dye according to table X).
  • the reaction was stirred (210 rpm) at 50° C. for 1 h.
  • Na2C03 was added periodically every 10 minutes (5 x 100 mg, after 10, 20, 30, 40 and 50 min reaction time).
  • the reaction mixture was stirred for another 10 min after the last addition of Na2C03.
  • the reaction solution was centrifuged at 4000 g at 4° C. for 15 min.
  • the pellet was resuspended and washed in ddH20 (40 g) 3 times and always centrifuged as before.
  • Example 23 Colorimetric Enzyme Assay for Detection of Myeloperoxidase Activity
  • Reagents like 3,4-diamino benzoic acid, 3-amino-4-hydroxy benzoic acid, 4-amino- 3-hydroxy benzoic acid, 2,3-diamino benzoic acid, 3,4-dihydroxy benzoic acid, 2-amino phenol, 2-amino-3-methoxy benzoic acid, Methyl-3,4-diaminibenzoate and 2-amino-4-methoxy phenol can be used for the detection of MPO activity (Table 2). Assay conditions: 1 mg/mL DABA or equivalent was dissolved in 100 mM sodium-phosphate-buffer (pH 6.4). H 2 O 2 was added to a final concentration of 5 mM.
  • the substrate/H 2 0 2 solution (95 ⁇ L) was added to a 96-well microtiter plate along with 5 ⁇ L of a MPO-containing sample.
  • the solution turned brownish upon MPO oxidation.
  • the reaction was monitored at 450 nm using a standard photometric plate reader.
  • Chimeric gene variants were synthesized encoding one to four concatemers of the hydrophilic carbohydrate binding module (CBM) from Cellobiohydrolase I ( Trichoderma reesei ), or the hydrophobic binding module (PDB) from Polyhydroxyalkanoate depolymerase ( Alcaligenes faecalis ).
  • CBM hydrophilic carbohydrate binding module
  • PDB hydrophobic binding module
  • Chimeric variants with the hydrophilic binding module (CBM) enable the attachment onto cellulose based filter papers/fabrics
  • chimeric variants with the hydrophobic binding module (PDM) enable the attachment onto PET (Polyethylene terephthalate) based strips.
  • TrxA- ElaSub 1_CBM_His fusion proteins were designed.
  • the construct consists of the trxA (thioredoxin) gene, a short spacer sequence that encodes a 6xHis-Tag [SEQ ID NO: 1] and the enterokinase cleavage site (Asp Asp Asp Lys) [SEQ ID NO: 2] for separating the TrxA fusion tag from the protein of interest. Subsequently to the enterokinase site, the newly designed elasub1_cbm coding sequence was introduced into the construct.
  • the elasub1 sequence encodes for amino acids that expose a lot of functional groups like thiol-, hydroxyl-, amino- or carboxy groups. These amino acids (cysteine, lysine, arginine, glutamine, asparagine, glutamic acid, aspartic acid, serine, threonine or tyrosine) should facilitate the coupling of dyes or pro-dyes to the chimeric peptides.
  • the coding sequence for the natural hydrophilic binding module (CBM) was located directly downstream to the elasub1 sequence, termed elasub1_cbm.
  • TrxA_ElaSub1_CBM-His fusion protein [SEQ ID NO: 9]:
  • Variant 1 ElaSub1_CBM.
  • the ElaSub 1 construct encodes a stretch of mainly hydrophilic amino acids.
  • the sequence for the natural hydrophilic binding module (CBM) is located directly downstream to the ElaSub1 protein sequence, termed ElaSub1_CBM.
  • ElaSub1_CBM The sequence for the natural hydrophilic binding module (CBM) is located directly downstream to the ElaSub1 protein sequence, termed ElaSub1_CBM.
  • a codon for cysteine is inserted.
  • the thiol group of the cysteine should facilitate the coupling of dyes or pro-dyes to the chimeric peptide.
  • two recognition/cleavage sites for HLE Al-Ala-Pro- Val
  • HLE Two recognition/cleavage sites for HLE
  • Enzymatic cleavage of the chimeric peptide through HLE should lead to the release of a peptide fragment that carries the coupled dye or pro-dye.
  • the HLE enzyme reaction should be visualized by binding the released peptide fragment through the charged groups of the dye.
  • the amino sequence of this variant is shown in table 4.
  • Variant 2 CatGSub1_CBM.
  • the CatGSub 1 construct encodes a stretch of mainly hydrophilic amino acids.
  • the sequence for the natural hydrophilic binding module (CBM) is located directly downstream to the ElaSub1 protein sequence, termed CatGSub1_CBM.
  • CBM hydrophilic binding module
  • a codon for cysteine is inserted into this region.
  • the thiol group of the cysteine should facilitate the coupling of dyes or pro-dyes to the chimeric peptide.
  • two recognition/cleavage sites for CatG (Ala-Ala-Pro-Phe) [SEQ ID NO: 4] are introduced into the hydrophilic spacer region.
  • certain dye molecules comprising positive or negative charged groups can be attached to the thiol group of the cysteine.
  • Enzymatic cleavage of the chimeric peptide through CatG should lead to the release of a peptide fragment that carries the coupled dye or pro-dye.
  • the CatG enzyme reaction should be visualized by binding the released peptide fragment through the charged groups of the dye.
  • the amino sequence of this variant is shown in table 4.
  • Variant 3 ElaSub1_CBM_His.
  • the ElaSub 1 construct encodes a stretch of mainly hydrophilic amino acids.
  • the sequence for the natural hydrophilic binding module (CBM) is located directly downstream to the ElaSub 1 protein sequence, termed ElaSub1_CBM.
  • ElaSub1_CBM The sequence for the natural hydrophilic binding module (CBM) is located directly downstream to the ElaSub 1 protein sequence, termed ElaSub1_CBM.
  • a codon for cysteine is inserted.
  • the thiol group of the cysteine should facilitate the coupling of dyes or pro-dyes to the chimeric peptide.
  • two recognition/cleavage sites for HLE Al-Ala-Pro- Val
  • HLE Two recognition/cleavage sites for HLE
  • Enzymatic cleavage of the chimeric peptide through HLE should lead to the release of a peptide fragment that carries the coupled dye or pro-dye. Through ionic exchange, the HLE enzyme reaction should be visualized by binding the released peptide fragment through the charged groups of the dye.
  • a repetitive sequence stretch encoding a His-tag [SEQ ID NO: 1] is attached subsequently to the sequence encoding the carbohydrate binding module. The amino sequence of this variant is shown in table 4.
  • Variant 4 CatGSub1 CBM His.
  • the CatGSub 1 construct encodes a stretch of mainly hydrophilic amino acids.
  • the sequence for the natural hydrophilic binding module (CBM) is located directly downstream to the ElaSubl protein sequence, termed CatGSub 1 CBM.
  • CBM hydrophilic binding module
  • a codon for cysteine is inserted into this region.
  • the thiol group of the cysteine should facilitate the coupling of dyes or pro-dyes to the chimeric peptide.
  • two recognition/cleavage sites for CatG (Ala-Ala-Pro-Phe) [SEQ ID NO: 4] are introduced into the hydrophilic spacer region.
  • certain dye molecules comprising positive or negative charged groups can be attached to the thiol group of the cysteine.
  • Enzymatic cleavage of the chimeric peptide through CatG should lead to the release of a peptide fragment that carries the coupled dye or pro-dye. Through ionic exchange, the CatG enzyme reaction should be visualized by binding the released peptide fragment through the charged groups of the dye.
  • a repetitive sequence stretch encoding a His-tag [SEQ ID NO: 1] is attached subsequently to the sequence encoding the carbohydrate binding module. The amino sequence of this variant is shown in table 4.
  • Variant 5 ElaSub2_CBM.
  • the ElaSub2 construct encodes a stretch of mainly hydrophilic amino acids.
  • the sequence for the natural hydrophilic binding module (CBM) is located directly downstream to the ElaSub2 protein sequence, termed ElaSub2_CBM.
  • ElaSub2_CBM The sequence for the natural hydrophilic binding module (CBM) is located directly downstream to the ElaSub2 protein sequence, termed ElaSub2_CBM.
  • CBM hydrophilic binding module
  • Enzymatic cleavage of the chimeric peptide through HLE should lead to the release of a peptide/peptides fragment/fragments that carry the coupled dye or pro- dye.
  • the HLE enzyme reaction should be visualized by binding the released peptide fragment/fragments through the charged groups of the dye.
  • the amino sequence of this variant is shown in Table 4.
  • Variant 6 CatGSub2_CBM.
  • the CatGSub2_CBM construct encodes a stretch of mainly hydrophilic amino acids.
  • the sequence for the natural hydrophilic binding module (CBM) is located directly downstream to the CatGSub2 protein sequence, termed CatGSub2 CBM.
  • CBM hydrophilic binding module
  • the thiol group of the cysteines should facilitate the coupling of dyes or pro-dyes to the chimeric peptide.
  • three recognition/cleavage sites for CatG (Ala-Ala-Pro-Phe) [SEQ ID NO: 4] are introduced into the hydrophilic spacer region.
  • certain dye molecules comprising positive or negative charged groups can be attached to the thiol group of the cysteines.
  • Enzymatic cleavage of the chimeric peptide through CatG should lead to the release of a peptide/peptides fragment/fragments that carry the coupled dye or pro- dye.
  • the CatG enzyme reaction should be visualized by binding the released peptide fragment/fragments through the charged groups of the dye.
  • the amino sequence of this variant is shown in Table 4.
  • Variant 7 ElaSub2_CBM_His.
  • the ElaSub2 construct encodes a stretch of mainly hydrophilic amino acids.
  • the sequence for the natural hydrophilic binding module (CBM) is located directly downstream to the ElaSub2 protein sequence, termed ElaSub2_CBM.
  • ElaSub2_CBM The sequence for the natural hydrophilic binding module (CBM) is located directly downstream to the ElaSub2 protein sequence, termed ElaSub2_CBM.
  • CBM hydrophilic binding module
  • Enzymatic cleavage of the chimeric peptide through HLE should lead to the release of a peptide/peptides fragment/fragments that carry the coupled dye or pro- dye. Through ionic exchange, the HLE enzyme reaction should be visualized by binding the released peptide fragment/fragments through the charged groups of the dye.
  • a repetitive sequence stretch encoding a His-tag [SEQ ID NO: 1] is attached subsequently to the sequence encoding the carbohydrate binding module. The amino sequence of this variant is shown in Table 4.
  • the CatGSub2_CBM construct encodes a stretch of mainly hydrophilic amino acids.
  • the sequence for the natural hydrophilic binding module (CBM) is located directly downstream to the CatGSub2 protein sequence, termed CatGSub2_CBM.
  • CBM hydrophilic binding module
  • the thiol group of the cysteines should facilitate the coupling of dyes or pro-dyes to the chimeric peptide.
  • three recognition/cleavage sites for CatG (Ala-Ala-Pro-Phe) [SEQ ID NO: 4] are introduced into the hydrophilic spacer region.
  • certain dye molecules comprising positive or negative charged groups can be attached to the thiol group of the cysteines.
  • Enzymatic cleavage of the chimeric peptide through CatG should lead to the release of a peptide/peptides fragment/fragments that carry the coupled dye or pro- dye. Through ionic exchange, the CatG enzyme reaction should be visualized by binding the released peptide fragment/fragments through the charged groups of the dye.
  • a repetitive sequence stretch encoding a His-tag [SEQ ID NO: 1] is attached subsequently to the sequence encoding the carbohydrate binding module. The amino sequence of this variant is shown in Table 5.
  • Variant 9 to variant 16 could be designed identically as variant 1 to variant 8 with the exception of changing the hydrophilic carbohydrate binding module (CBM) against the hydrophobic binding module (PDB).
  • CBM hydrophilic carbohydrate binding module
  • PDB hydrophobic binding module
  • Table 5B Nucleotide sequence of the chimeric gene variants with the hydrophile carbohydrate binding module. All eight constructs were cloned into a pET-32b(+) expression vector (Novagen) using the Nco I and Xho I restriction sites located in the MCS of the cloning vector.
  • Elasubl CBM [SEQ ID NO: 191 ElaSub1_CBM ATGGGTGGTAGCTGCGGTGGTGGTGGTAGCGCAGCACCGGTTGGTGGTGGCGGTTCGCTGCTC CTGTGGGTGGCGGTGGTTCACCGCCTGGTGGTAATCGTGGTACAACCACCACCCGTCCGC AACCACAACCGGTAGCAGTCGGGTCCGACCAGAGCCATTATGGTCAGTGTGGTGGAGGT AACCACAACCGETAGCAGTCCGGGTCCCGACCCAGAGCCATTATGGTCAGTGTGGTGGTATTGGT TATAGCGG7CCGACCGTTTGTGCAAGCGGCACCACCACCTGTCAGGTTCTGAATCCGTAT7ATAGCC AGTGTCTG
  • Example 25 Expression of Elastase (HLE) Substrates With Polymer Binding Sequences.
  • Variant 3 (Example 9): BL21 Gold (DE3) [pET32b(+)ela Sub1_cbm His]
  • the chimeric gene was cloned into a pET32b(+) expression system using Ncol and Xhoi restriction sites/enzymes.
  • Final protein expression of the chimeric peptide was carried out in E. coli BL21 Gold (DE3), a protease deficient expression host, which enables a proper protein expression based on the T7 promoter of the pET32b(+) expression vector.
  • the proper protein expression of the recombinant protein was monitored with SDS-PAGE, compared to the identically expressed empty pET32b(+) vector.
  • Purification of the chimeric construct from crude lysate was done using the IBA -NTA sepharose gravity flow column (1 ml) according to the IBA protocol. Fractions containing the purified protein were examined using SDS-PAGE. In order to prevent protein exposure to the high imidazole concentration after elution, buffer exchange was carried out using PD 10 desalting columns from GE Healthcare. The yield of the purified chimeric fusion construct could be calculated with 30 mg protein per 2 g initial cell pellet.
  • the recombinant expressed bovine enterokinase from Merck Millipore was used.
  • the separation of the desired chimeric construct from the TrxA-Tag was verified by SDS-PAGE.
  • the finished chimeric construct was adsorbed onto a cellulose based filter paper (or fabrics) through the hydrophilic carbohydrate binding module.
  • the filter strip containing the chimeric peptide was incubated for 30 min with a 0.1 M sodium phosphate buffer solution (pH 7.4), containing 0.05 U/ml HLE, as well as with human wound fluids.
  • a 0.1 M sodium phosphate buffer solution pH 7.4
  • a 0.1 M sodium phosphate buffer solution pH 7.4
  • 0.05 U/ml HLE containing 0.05 U/ml HLE
  • Initially non coloured samples (clear supernatant) that exhibit elastase activity developed a blue colour, depending on the attached dye. Due to enzymatic cleavage at one or both of the internal HLE restriction sites (Ala-Ala-Pro-Val), peptide fragments with the attached Remazol Brilliant Blue dye molecules get uncoupled, resulting in a blue coloured supernatant.
  • chimeric constructs with the hydrophobic binding module can be used for adsorption of PET (Polyethylene terephthalate) based carrier materials.
  • PET Polyethylene terephthalate
  • the PDM group can be interchanged with the CBD in a manner described before.
  • the polyhydroxybutyrate depolymerase from A. faecalis (PBM or PDM) sequences are described in Ribitsch et al., “Fusion of Binding Domains to Thermobifida cellulosilytica Cutinase to Tune Sorption Characteristics and Enhancing PET Hydrolysis,” Biomacromolecules , 14 (6), pp 1769-1776, 2013.
  • the disclosure in Ribitsch is incorporated by reference herein in its entirety. Analogously, any solid phase binding domain can be used in this manner.
  • Other types of CBD peptides may be employed interchangably to achieve the desired functionality.
  • the constructs disclosed herein comprise a non-soluble ancher like CBD, this can be interchanged with other anchors, notably other CBDs or PDMs. Smaller anchors are preferred for stoiciometric reasons.
  • elastase As exemplified herein, has broad preferences, wherein AAPV [SEQ ID NO: 3] sequence is most preferred, however, AAPF [SEQ ID NO: 4] is almost the same in terms of turnover and AAAA [SEQ ID NO: 4] is similar. Thus, anyone of these sequences could be exchanged for the other without loss of function.
  • Cyteines are particularly employed as a means to anchor dyes and particularly not more than one per construct, preferably one per cutting site. They should be distal from the cutting sites to ensure that the sulfonated dye does not interact with the enzyme more than necessary.
  • elastase is a basic enzyme and it is inhibited by strong negatively charged groups. This means that more than one sulfonated dye per cutting site is not required. It is desirable that the number of sulfonate groups is lower than 4 per cutting site. With greater number of such sulfonate groups, there is a risk that they will mask access to the cutting site.
  • Trx-Ela-Subl Purified and lyophilised Trx-Ela-Subl was dissolved in 3 ⁇ 40 (0.01 g/2.5 ml) (protein concentration ⁇ 0.2 mg/ml). The buffer was exchanged from Tris-HCl to a Na 2 P0 4 /Na 2 S0 4 solution using a PD-10 column.
  • the stained and purified peptide construct was applied on a cellulose surface and dried at 37° C. for 2 h. Unbound Trx-Ela-Sub 1-RBB was removed with H 2 0. The stripes with the applied Elastase substrate were incubated with and without Elastase containing buffer, respectively. The Elastase responsive dye release can be seen in FIG. 10 .
  • Example 28 3-Step-Immobilisation of Bromocresol Purple Onto OH-Rich Surfaces Like Cellulose as pH Indicator.
  • Step Soaking of OH-rich surface (e.g. cellulose) in reaction solution. Incubation of soaked material at 80 - 120° C. for 5-20 min.
  • OH-rich surface e.g. cellulose
  • Step 3 Bromocresol purple (0.1 - 3.3 mg/ml) applied on pretreated material and dried at 120° C. for 20 min.
  • p-Nitrophenylphosphorylcholine as substrate for Phospholipase C was used.
  • p-Mtrophenylphosphorylcholine is dissolved in water (50-100 mM).
  • 230 ⁇ l of the buffer and 100 ⁇ l of the substrate are pipetted into a microtiterplate.
  • Diagnosis A volume between 5 and 12 ⁇ L of wound fluid sample is added to the test system, preferentially between 8 and 10 ⁇ L and mixed by manual shaking for 10 seconds. This mixture is incubated at room temperature for 30 minutes. Thereafter, infection will be indicated by a colour change from colourless to yellow.
  • Infected wound fluid samples A, B, C
  • non-infected samples D, E, F
  • IA Visual inspection of the samples after 30 minutes of incubation indicated a colour change to yellow only for infected samples A, B, and C.
  • Example 30 Phospholipase A2 Based Test - Liquid System
  • Diagnosis A volume between 5 and 12 pL of wound fluid sample is added to the test system, preferentially between 8 and 10 ⁇ l and mixed by manual shaking for 10 seconds. This mixture is incubated at room temperature for 30 minutes. Thereafter, infection will be indicated by a colour change from colourless to yellow.
  • Example 31 Catalase Based Test - Liquid System
  • Purpald as substrate for Catalase was used. Purpalt is dissolved in water (50-100 mM). 200 ⁇ l of substrate solution are pipetted into a microtiterplate.
  • Diagnosis A volume between 5 and 12 ⁇ L of wound fluid sample is added to the test system, preferentially between 8 and 10 ⁇ l and mixed by manual shaking for 10 seconds. This mixture is incubated at room temperature for 30 minutes. Thereafter, infection will be indicated by a colour change from colourless to dark violet.
  • a material containing substrates for one or more of MPO, elastase, lysozyme, phospholipase, and catalase and optionally a pH indicator is contacted with a body fluids such as wound, tear, vitreal, CSF, airway aspirates or sputum, synovial, blood, plasma, serum, urine, peritoneal, interstitial, subcutaneous, bile, intestinal or similar fluids. Samples from infected organisms or tissues tend to show a higher degree of reaction. A combination of one or more of the reactions is used to detect the infection and its degree.
  • N-methoxysuccinyl-ala-ala-pro-val-p- nitroanilide dissolved at a concentration of 20 mM in DMSO in 0.1 M HEPES buffer (pH 7.4, containing 0.5 M NaCl) is pipetted into a transparent eppendorf tube.
  • the final concentration of N- methoxysuccinyl-ala-ala-pro-val-p-nitroanilide can be between 0.05 to 2.50 mM, and is preferentially between 0.80 and 1.20 mM.
  • a volume between 1 and 15 L of sputum sample is added to the test system, preferentially between 2-5 ⁇ L. and mixed by manual shaking for 10 seconds.
  • Example 34 Elastase Based Test - Cellulose Paper Based System
  • N-methoxysuccinyl-ala-ala-pro-val-p-nitroanilide is dissolved at a concentration of 281 mM in dimethoxysulfoxide. 2-5 ⁇ l of this solution, preferentially 2 ⁇ l were pipetted onto Whatman-Filterpapier.
  • test system of Whatman-Filterpapier incubated with N-methoxysuccinyl-ala-ala-pro-val-p-nitroanilide is then incubated with 1-5 ⁇ l, preferentially 2 ⁇ l sputum sample and 2 ⁇ l 2 ⁇ l NaCl (50 mM) and incubated at room temperature for 5 minutes. Thereafter, infection will be indicated by a colour change of the filterpaper to yellow. Non infected sputum samples will not change colour.
  • infected samples (A, B) and non infected samples (C, D) were taken and placed into the diagnostic system described in 1C containing the substrate mM N-methoxysuccinyl-ala-ala-pro-val-p-nitroanilide .
  • Example 35 Cathepsin Based Test - Liquid System
  • N-succinyl-ala-ala-pro-phe-p-nitroanilide is dissolved at a concentration of 20 mM in dimethoxysulfoxide and diluted in 0.1 M HEPES buffer (pH 7.4, containing 0.5 M NaCl).
  • the final concentration of N-methoxysuccinyl-ala-ala-pro-phe p-nitroanilide can be between 0.5 to 5 mM, and is preferentially 3 mM.
  • a volume between 1 and 5 ⁇ L of sputum sample is added to the test system, preferentially 2-4 uL and mixed by manual shaking. This mixture is incubated at 37° C. for 20 minutes. Thereafter, infection will be indicated by a colour change to yellow. Mixtures containing non infected samples will not change colour.
  • Example 36 Cathepsin Based Test - Cellulose Based System
  • N-methoxysuccinyl-ala-ala-pro-phe-p-nitroanilide is dissolved at a concentration of 20 mM in dimethoxysulfoxide and diluted in 0.1 M HEPES buffer (pH 7.4, containing 0.5 M NaCl).
  • the final concentration of N-methoxysuccinyl-ala-ala-pro-phe-p- nitroanilide can be between 0.5 to 10 mM, and is preferentially 5.00 mM. 10 ⁇ L of this solution were pipetted onto Whatman filter paper.
  • test system of Whatman-Filterpapier incubated with N-methoxysuccinyl-ala-ala-pro-val-p-nitroanilide is then incubated with 1-5 ⁇ l preferentially 2 ⁇ l sputum sample and 2 ⁇ l 2 ⁇ l NaCl (50 mM) and incubated at room temperature for 20 minutes. Thereafter, infection will be indicated by a colour change of the filterpaper to yellow. Non infected sputum samples will not change colour,
  • infected samples (A, B) and non- infected samples (C, D) were taken and placed into the diagnostic system described in 1C containing the substrate mM -methoxysuccinyl-ala-ala-pro-val-p-nitroanilide .
  • Example 37 Myeloperoxidase Based Test - Liquid System
  • TMB TMB
  • ABTS ABTS
  • Guaiacol 4-Amino-3 -methoxy benzoic acid
  • Fast Blue RR 3350 ⁇ l of succinate buffer (pH 5.4) comprising 0.3 M sucrose 15 ⁇ l 1% H202 and 7 ⁇ l of the substrates (5-40 mM ABTS, 20-150 mM TMB, 0.025 mM of Fast Blue RR, 10-50 mM 4- Amino-3 -methoxy benzoic acid and 10-20 mM Guaiacol) were added.
  • TMB (3, 3′, 5, 5′ -Tetramethylbenzidine) is firstly dissolved in N, N- Methylformamide, Fast Blue RR is dissolved in ethanol, while ABTS can be dissolved in water and 4- Amino-3 -methoxy benzoic acid is dissolved in DMSO. Guaiacol. 100 ⁇ l of the solutions are pipetted into a microtiterplate.
  • a volume between 1 and 7 pL of sputum sample is added to the test system, preferentially between 4-6 pL and mixed by manual shaking for 10 seconds. This mixture is incubated at room temperature for 10 minutes. Thereafter, infection will be indicated by a colour change from colourless to blue (TMB or green (ABTS), respectively and to brown to red (4-Amino-3 -methoxy benzoic acid and Guaiacol) Mixtures containing non infected samples will not change colour
  • Infected Sputum samples of (A, B, C) and non infected sputum samples (D, E, F) are incubated with the diagnostic system described in IA containing the different substrates. Visual inspection of the samples after 5 minutes of incubation indicated a colour change to blue in case of TMB only for infected samples A, B, and C.
  • Example 38 Myeloperoxidase Based Test - Cellulose Based System
  • test system of Whatman-Filterpapier incubated with the different MPO substrates is then incubated with 1 -5 ⁇ l preferentially 2 ⁇ l sputum sample and incubated at room temperature for 5 minutes. Thereafter, infection will be indicated by a colour change of the filterpaper to blue, green or brown-red. Non infected sputum samples will not change colour.
  • infected samples (A, B) and non infected samples (C, D) were taken and placed into the diagnostic system described in 1C containing the substrates TMB, ABTS, Fast Blue RR, Guaiacol and 4A3Mba. Visual inspection of the samples after 5 minutes of incubation indicated a colour change to brown (4A3Mba) in case of for infected samples A, B.
  • Example 39 Phospholipase A2 Based Test - Liquid System
  • 4-Nitro-3-octanoylbenzoic acid as Phospholipase A2 - substrate was used.
  • 4-Nitro-3-octanoylbenzoic acid (1.7 mM) is dissolved in assay buffer containing 50 mM Tris/HCl buffer pH 7.2, 150 mM KCL and 10 mM CaC12. 190 ⁇ l of the buffer are pipetted into a microtiterplate.
  • a volume between 5 and 12 ⁇ L ⁇ o ⁇ sputum wound fluid sample is added to the test system, preferentially between 8 and 10 ⁇ l and mixed by manual shaking for 10 seconds. This mixture is incubated at room temperature for 30 minutes. Thereafter, infection will be indicated by a colour change from colourless to yellow.
  • Infected sputum samples (A, B) and non infected samples (E, F) are incubated with the diagnostic system described in IA. Visual inspection of the samples after 30 minutes of incubation indicated a colour change to yellow only for infected samples A, B, and C.
  • Example 40 Catalase Based Test - Liquid System
  • Purpald as substrate for catalase was used. Purpalt is dissolved in water (50-100 mM?). 200 ⁇ l of substrate solution are pipetted into a microtiterplate.
  • a volume between 5 and 12 ⁇ L of sputum sample is added to the test system, preferentially between 8 and 10 ⁇ l and mixed by manual shaking for 10 seconds. This mixture is incubated at room temperature for 30 minutes. Thereafter, infection will be indicated by a colour change from colourless to dark violet.
  • Infected wound fluid samples A, B, C
  • non-infected samples D, E, F
  • IA Visual inspection of the samples after 30 minutes of incubation indicated a colour change to violet only for infected sputum samples A, B, and C.
  • Example 41 Lysozyme Based Test - Liquid System
  • Micrococcus lysodeikticus pep- tidoglycan is suspended in 15 ml 0.1 M KH2PO4 buffer (pH 7.0) . Preferentially, an amount between 8 and 10 mg is suspended. 290 ⁇ L of this solution is pipetted into a transparent microtiterplate.
  • a volume of 10 ⁇ L of sputum is added to the test system and mixed by manual shaking for 10 seconds. This mixture is incubated at 37° C. for 15 minutes. Thereafter, infection will be indicated by a decrease in turbidity. Mixtures containing non infected samples will not change.

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