WO2018071506A1 - Composition destinée à la désintégration de biofilms, procédés de fabrication associés et articles comprenant ladite composition - Google Patents

Composition destinée à la désintégration de biofilms, procédés de fabrication associés et articles comprenant ladite composition Download PDF

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Publication number
WO2018071506A1
WO2018071506A1 PCT/US2017/056087 US2017056087W WO2018071506A1 WO 2018071506 A1 WO2018071506 A1 WO 2018071506A1 US 2017056087 W US2017056087 W US 2017056087W WO 2018071506 A1 WO2018071506 A1 WO 2018071506A1
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WIPO (PCT)
Prior art keywords
composition
biofilm
calcium
amount
water
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PCT/US2017/056087
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English (en)
Inventor
Ethan Eugene Mann
Binjie XU
Michael Ryan Mettetal
Rhea M. MAY
David Fujimoto
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Sharklet Technologies, Inc
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Publication of WO2018071506A1 publication Critical patent/WO2018071506A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/54—Mixtures of enzymes or proenzymes covered by more than a single one of groups A61K38/44 - A61K38/46 or A61K38/51 - A61K38/53
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
    • C11D3/00—Other compounding ingredients of detergent compositions covered in group C11D1/00
    • C11D3/16—Organic compounds
    • C11D3/38—Products with no well-defined composition, e.g. natural products
    • C11D3/386—Preparations containing enzymes, e.g. protease or amylase

Definitions

  • This disclosure relates to a composition for biofilm disruption, methods of manufacture thereof, and to articles comprising the same.
  • Biofilms are communities of microorganisms (also referred to herein as microbes) protected by a self-synthesized layer of complex polysaccharides, proteins, lipids and extracellular DNA, collectively called the extracellular polymeric substance (EPS).
  • EPS extracellular polymeric substance
  • microorganisms by providing more diverse adhesion sites to a substrate. Being in a biofilm provides these microorganisms with a host of advantages, including, but not limited to: physical protection from the host immune system and antimicrobials/antibiotics, retention of water and tolerance to desiccation, nutrient sorption and storage, high extracellular enzymatic activity, adhesion to the infection site and cell aggregation, leading to a coordination of their virulence factor expression via quorum sensing.
  • biofilm-associated particularly troubling to the medical field is that it has been estimated that as much as 80% of all human bacterial infections are biofilm-associated, including more than 90% of all chronic wound infections. Additionally, the biofilm mode of microbial life is responsible for up to a 1000-fold increase in antibiotic tolerance due to the physical impedance and enzymatic inactivation of the drugs, coupled with lowered metabolic rates in many biofilm-associated cells. Thus, biofilm infections are highly recalcitrant and are associated with chronic, non-healing infections.
  • dispersal agents Nearly all mature biofilms undergo dispersal, which can be divided into two main subtypes: passive and active, both of which result in the release of planktonic, free-floating cells into the environment.
  • Passive dispersal simply refers to a physical sloughing event brought on by external forces such as fluid and solid shear, and mechanical interventions (e.g., tooth brushing).
  • a biofilm streamer may be torn off of the main mass of the biofilm by the flow of interstitial fluid or due to physical abrasion by a surgeon. This results in aggregates of microorganisms that cannot be accurately identified or quantified. Typically inaccurate disaggregation results in under-representing the true microbial load.
  • Active dispersal refers to dispersal events triggered by the biofilm microbes themselves in response to environmental changes such as nutrient starvation, toxic byproducts, bacteriophages, phagocyte challenge, antimicrobial stress, and unfavorable oxygen levels.
  • active dispersal is a vital stage in the life-cycle of a biofilm that contributes to bacterial survival and disease progression. Active dispersal in
  • Microbial quantification has relied on culture methods to grow microscopic organisms into larger colonies or plaques. This method relies also on suspending organisms in liquid and serially diluting the organisms until only about 1 to 100 organisms remain in solution. Once these relatively few organisms remain in solution, they may be spread onto semi-solid growth media and allowed to form colonies or plaques. This process was relatively straight-forward until research demonstrated how intensely dense and compact biofilm-embedded microorganisms are.
  • composition for disaggregating biofilms comprising a plurality of enzymes; a calcium salt that prevents activity inhibition in the enzymes; a surfactant; and a pH adjusting additive.
  • Disclosed herein is a method comprising mixing a plurality of enzymes; a calcium salt; a surfactant; a pH adjusting additive and water to form a disaggregation composition.
  • Figure 1 is a graph that depicts the efficacy of the previous method of quantification using only mechanical disaggregation versus the inventive composition.
  • a biofilm is a dense colonization of organisms encased in an extracellular matrix commonly tolerant of antimicrobial compounds and antiseptic agents.
  • a microorganism is a small single-cell organism invisible to the naked eye.
  • a composition is a mixture of components contained in a single solution.
  • Disaggregation as defined herein includes the breaking up of complexes of multiple small units into individual units capable of being suspended in a homogeneous solution.
  • composition also referred to herein as a composition
  • a composition that is designed to break apart (disaggregate or disperse) microorganisms contained in a biofilm.
  • the biofilm may contain either a single species or multiple species that differ from one another. This disaggregation of microorganisms occurs while maintaining microbial viability and individual microbial cell characteristics of the biofilm.
  • the composition comprises enzymes that allow for accurate quantification of microorganisms present in biofilms after disaggregation.
  • Biofilm quantification (while preserving the viability of colony forming units of microorganisms) is generally challenging due to the clumping characteristics of organisms embedded in or on biofilms. This quantification is useful for accurate clinical diagnosis using patient biopsy samples, animal samples for either veterinary clinical practice or preclinical research animals, and in vitro biotechnology research and development.
  • Tissue-embedded biofilms i.e., biofilms that are embedded in tissues in the bodies of living beings or in tissues outside the bodies of living beings contained in a laboratory setting
  • tissue-degrading enzymes that permits disaggregation of microbes that comprise cells of non-microbial origin.
  • Standard test methods include disaggregating biofilms using mechanical methods.
  • the use of a composition that comprises enzymes would provide more accurate information than from existing mechanical methods.
  • This composition may be used on biofilm from in vitro experiments or in in vivo or ex vivo tissue-embedded biofilms.
  • the composition for disaggregation of a biofilm comprises a plurality of enzymes, a calcium salt for maintaining the activity of at least one of the enzymes in the plurality of enzymes, a surfactant, and a pH adjusting additive.
  • the enzyme may target one or more of proteins, polysaccharides, nucleic acids, starches, or collagens. Combinations of enzymes may also be used. All of the foregoing ingredients of the composition are dispersed in primarily in water to form a single phase solution. Other solvents and additives may be added to the composition as desired.
  • the protease in the composition comprises Proteinase K.
  • Proteinase K cleaves peptide bonds adjacent to the carboxylic group of aliphatic and aromatic amino acids and is useful for general digestion of protein in biological samples. It is desirable for the Proteinase K to be purified to remove RNase (ribonuclease) and Dnase (deoxyribonuclease) activities.
  • the Proteinase K is present in the composition to disrupt and cleave proteins present in the biofilm thus releasing the microorganisms to be homogeneously resuspended.
  • the Proteinase K is present in an amount of 0.01 to 15 milligrams per milliliter, preferably 0.05 to 10 milligrams per milliliter, 0.1 to 4 milligrams per milliliter and more preferably 0.3 to 1.0 milligrams per milliliter based on the amount of water in the composition.
  • a variety of polysaccharides hydrolases may optionally be used in the composition.
  • An exemplary polysaccharide hydrolase is Dispersin B that is used to target polysaccharides present in the biofilm.
  • Dispersin B also known as DspB or DispersinB
  • the bacteria secrete Dispersin B to release adherent cells from a mature biofilm colony by disrupting biofilm formation.
  • the enzyme catalyzes the hydrolysis of linear polymers of N-acetyl-D-glucosamines found in the biofilm matrices.
  • Poly-acetyl glucosamines are integral to the structural integrity of the biofilms of various Gram-positive bacteria and Gram-negative bacteria and are referred to as PIA (PNAG,PS/A) in
  • Dispersin B allows for the release of microorganisms that can adhere to adjacent new surfaces and extend the biofilm or start new colonies.
  • the Dispersin B is used in an amount of 0.01 to 150 micrograms per milliliter, preferably 0.05 to 125 micrograms per milliliter, and preferably 0.1 to 100 micrograms per milliliter of water in the composition.
  • the enzymes in the composition also include a deoxyribonuclease (Dnase).
  • Dnase is any enzyme that catalyzes the hydrolytic cleavage of phosphodiester linkages in the DNA backbone, thus degrading DNA.
  • Deoxyribonucleases are one type of nucleases, a generic term for enzymes capable of hydro lyzing phosphodiester bonds that link nucleotides.
  • the enzyme is Deoxyribonuclease I (Dnase I).
  • Dnase I is an endonuclease coded by the human gene Dnase 1.
  • Dnase I is a nuclease that cleaves DNA preferentially at phosphodiester linkages adjacent to a pyrimidine nucleotide, yielding 5 '-phosphate-terminated polynucleotides with a free hydroxyl group on position 3', on average producing tetranucleotides.
  • the Dnase I is used to target nucleic acids present in the composition.
  • the Dnase I is used to target deoxyribonucleic acid (DNA).
  • the Dnase I is present in an amount of 0.1 to 20 kilo Units of activity
  • the Dnase I is present in the composition in an amount of 1 to 50 micrograms per milliliter, preferably 2 to 40 micrograms per milliliter and more preferably 5 to 30 micrograms per milliliter of water in the composition.
  • Enzymes such as collagenase and amylase may also optionally be used in the composition if desired.
  • Collagenase is used to target collagen present in the biofilm while amylase is used to target starch present in the biofilm.
  • Collagen is present in an amount of 10 to 300 U/milliliter of water in the composition.
  • the composition comprises a calcium salt to facilitate the protection of Dnase I from Proteinase K.
  • the calcium salt facilitates a reduction in the inhibition of specific activities of certain enzymes.
  • preservatives such as (Ethylenediaminetetraacetic acid) EDTA
  • Dnase I is rapidly inactivated by proteinase K.
  • the presence of calcium salts prevents the inactivation of the Dnase I by proteinase K.
  • Examples of calcium salts are calcium chloride, calcium sulfate, calcium nitrate, calcium bicarbonate, calcium citrate, calcium phosphate, or a combination thereof.
  • Calcium salts may be used in amounts of 2 to 40 millilmolar (mM), preferably 3 to 30 millimolar, preferably 5 to 20 millimolar, and more preferably 7 to 13 millimolar.
  • the calcium salt concentration is based on the amount of water in the composition.
  • Acids, bases and salts may also be used in the composition to maintain the pH of the composition to between 6.5 and 8.
  • acids are phosphoric acid, sulfuric acid, nitric acid, acetic acid, hydrochloric acid or a combination thereof.
  • bases are sodium hydroxide, potassium hydroxide, ammonium hydroxide, or a combination thereof.
  • Salts may be added to maintain the pH of the composition. These are termed primary salts.
  • secondary salts may also be added to neutralize the iodine and the chlorine.
  • primary salts are sodium chlorides, sodium phosphates, sodium carbonates, sodium dihydrogen carbonates, sodium sulfate, sodium nitrate, or a combination thereof.
  • the salt is monosodium dihydrogen orthophosphate (NaH2P04), disodium hydrogen phosphate
  • the salt is added to the composition in an amount of 0.01 M to 0.2 M, preferably 0.05 M to 0.15 M.
  • the salt concentration relates to water present in the composition.
  • secondary salts are sodium thiosulfate.
  • the sodium thiosulfate is used to neutralize iodine and chlorine present in the composition as these two cytotoxic agents might be present in in vitro or in/ex vivo samples.
  • the secondary salt is also operative to inactivate cytotoxic agents in the biofilm samples.
  • the secondary salt e.g., sodium thiosulfate
  • the primary and secondary salt concentrations are with respect to the water content of the composition.
  • Surfactants may also be used in the composition.
  • the surfactants include nonionic, cationic, anionic and zwitterionic surfactants that can be electron donating or electron accepting and can include cyclic, linear, or branched molecules. Many long chain alcohols exhibit some surfactant properties. Prominent among these are the fatty alcohols, cetyl alcohol, stearyl alcohol, and cetostearyl alcohol (consisting predominantly of cetyl and stearyl alcohols), and oleyl alcohol. Examples include polyethylene glycol alkyl ethers, octaethylene glycol monododecyl ether, pentaethylene glycol monododecyl ether,
  • polypropylene glycol alkyl ethers polypropylene glycol alkyl ethers, glucoside alkyl ethers, decyl glucoside, lauryl glucoside, octyl glucoside, polyethylene glycol octylphenyl ethers, Triton X-100, Tween-80, sodium thiosulfate, polyethylene glycol alkylphenyl ethers, Nonoxynol-9, glycerol alkyl esters, glyceryl laurate, polyoxyethylene glycol sorbitan alkyl esters, polysorbate, sorbitan alkyl esters, sorbitan trioleate, cocamide MEA, cocamide DEA, dodecyldimethylamine oxide, block copolymers of polyethylene glycol and polypropylene glycol, poloxamers,
  • POEA polyethoxylated tallow amine
  • Anionic surfactants contain anionic functional groups at their head, such as sulfate, sulfonate, phosphate, and carboxylates.
  • Cationic surfactants include pH-dependent primary, secondary, or tertiary amines.
  • Zwitterionic (amphoteric) surfactants have both cationic and anionic centers attached to the same molecule. The cationic part is based on primary, secondary, or tertiary amines or quaternary ammonium cations.
  • the anionic part can be more variable and include sulfonates, as in the sultaines CHAPS (3-[(3- Cholamidopropyl)dimethylammonio]- 1 -propanesulfonate) and cocamidopropyl
  • Betaines such as cocamidopropyl betaine have a carboxylate with the ammonium.
  • the most common biological zwitterionic surfactants have a phosphate anion with an amine or ammonium, such as the phospholipids phosphatidylserine,
  • phosphatidylethanolamine phosphatidylcholine
  • sphingomyelins phosphatidylcholine
  • Preferred surfactants include succinimides, poly-isobutylene succinimide (e.g., Chevron product OLOA11000), octylamine, trioctylamine, Tween-80, S-49, sorbitan trioleate, sodium thio sulfate, non-ionic surfactants that include hydrophilic polyethylene oxide chains on a hydrocarbon oleophilic group.
  • succinimides e.g., Poly-isobutylene succinimide (e.g., Chevron product OLOA11000), octylamine, trioctylamine, Tween-80, S-49, sorbitan trioleate, sodium thio sulfate, non-ionic surfactants that include hydrophilic polyethylene oxide chains on a hydrocarbon oleophilic group.
  • the surfactants facilitate the formation of a composition in a single phase.
  • the surfactant is added to the composition in an amount of 1 to 20 grams per liter, preferably 2 to 10 grams per liter of water.
  • Table 1 lists the potential components, known molecular targets, and concentration ranges for an exemplary disaggregation composition. The appropriate components may be combined into an aqueous-based composition at appropriate
  • the aqueous solution may contain appropriate buffers for enzyme interaction or material suspension.
  • Another construction of the composition could be in a lyophilized form where the enzymes are more stable in a powder that is reconstituted in a buffer or appropriate liquid.
  • Table 1 shows the composition of one biofilm-disaggregation composition.
  • Table 2 reflects another composition that may be used for the disaggregation of biofilms.
  • the plurality of enzymes, the calcium salt for maintaining the activity of at least one of the enzymes in the plurality of enzymes, primary and secondary salts, the surfactant, and the pH adjusting additive are mixed together in a reactor.
  • the ingredients listed above may be mixed for a period of 1 to 20 minutes at room temperature and stored at 4°C for use when desired.
  • Certain ingredients used in the composition would be produced through biological production from bacteria or yeast and purified using typical protein production methods. Following production of individual components, the composition would be completed by mixing the individual components.
  • composition after mixing it is desirable for the composition after mixing to have a pH of 6.5 to 8.0, preferably 6.8 to 7.5.
  • Table 3 lists one method of using the composition for disaggregating a biofilm.
  • the method for using the disaggregation composition will be to expose the biofilm- embedded microorganisms to the solution while applying mechanical disruption. For example, skin or soft tissue samples with suspected biofilm-embedded microorganisms will be dropped into the proposed disaggregation composition and the sample is blended, sonicated, and vortexed to homogenize the tissue and suspected microorganisms.
  • Table 3 provides a summary of the method using a disaggregation composition for quantification of biofilm- embedded microorganisms from tissue biopsy
  • the mixture may be mixed in a mixer such as a sonicator or a vortex homogenizer.
  • the mixture is incubated at a temperature of 37°C for 12 to 24 hours.
  • the mixing in the mixer may be repeated several times.
  • the mixture is then diluted in several steps up to a weight ratio of 1 : 10 in a phosphate-buffered saline solution.
  • the composition of a phosphate-buffered saline solution comprises sodium chloride, potassium chloride and sodium phosphates.
  • the dilution step may be conducted up to 8 times. In other words, the dilution step may be repeated up to 8 times till the desired dilution is achieved.
  • the diluted sample is then spread on a substrate (a plate) for up to 3 times to achieve accurate quantification. Quantification is generally accomplished by enumeration of colonies after incubation at a selected temperature ranging between 22°C and 37°C for a chosen duration. The duration may be from 12 to 24 hours. This duration is sometimes referred to as an incubation period.
  • the composition disclosed herein may be used advantageously over other processes for disaggregating biofilms. Previously used mechanical disaggregation is insufficient for complete disaggregation of biofilm-embedded microorganisms.
  • Enzymatic methods for disaggregation or targeting a single molecule or organism-based matrix component will result in incomplete separation of microorganisms from other microorganism or other tissues.
  • microorganisms are killed and this precludes accurate quantification of the microorganisms in the biofilm.
  • Figure 1 describes the efficacy of the previous method of quantification using only mechanical disaggregation.
  • Control and anti-biofilm test surfaces were evaluated by bacterial loads in the experiment. The same bacterial load was applied to each test type, but only the samples with Proteinase K added to the quantification process resulted in accurate sampling. The difference between the control and control + Proteinase K is approximately 1.5 logs of bacteria meaning that 1.5 logs of bacteria are under-reported without the use of an enzymatic additive to disrupt the biofilm.
  • the anti-biofilm test surface was not able to demonstrate avoidance of biofilm without proteinase K.

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  • Health & Medical Sciences (AREA)
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  • Chemical & Material Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Gastroenterology & Hepatology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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Abstract

L'invention concerne une composition destinée à désagréger des biofilms consistant en une pluralité d'enzymes ; un sel de calcium qui empêche une inhibition d'activité dans les enzymes ; un tensioactif ; et un additif d'ajustement de pH. L'invention concerne également un procédé consistant à mélanger une pluralité d'enzymes ; un sel de calcium ; un tensioactif ; un additif d'ajustement de pH et de l'eau en vue de former une composition de désagrégation.
PCT/US2017/056087 2016-10-11 2017-10-11 Composition destinée à la désintégration de biofilms, procédés de fabrication associés et articles comprenant ladite composition WO2018071506A1 (fr)

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US62/406,524 2016-10-11

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110623060A (zh) * 2019-10-31 2019-12-31 福州大学 一种蛋白酶k在鲜鱼制品保鲜中的应用

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008043175A1 (fr) * 2006-10-13 2008-04-17 Kane Biotech Inc. COMPOSITIONS D'ANTIBIOFILMS À BASE DE b-N-ACÉTYLGLUCOSAMINIDASE SOLUBLE ET LEURS UTILISATIONS
US20080139545A1 (en) * 2006-05-22 2008-06-12 Won-Taek Choe Formulation to treat ear infection
US20090238923A1 (en) * 2007-11-05 2009-09-24 Danisco Us Inc., Genencor Division Variants of bacillus licheniformis alpha-amylase with increased thermostability and/or decreased calcium dependence
US20110054026A1 (en) * 2008-05-22 2011-03-03 Michael Patrick Doyle Antimicrobial composition and use
US20110086101A1 (en) * 2008-04-03 2011-04-14 Srinivasa Madhyastha Dispersinb, 5-Fluorouracil, Deoxyribonuclease I and Proteinase K-Based Antibiofilm Compositions and Uses Thereof
US20130052250A1 (en) * 2010-02-12 2013-02-28 University Of Newcastle Upon Tyne Compounds and methods for biofilm disruption and prevention
US20150118219A1 (en) * 2012-05-11 2015-04-30 Smith & Nephew, Inc. Use of seaprose to remove bacterial biofilm
WO2015100331A2 (fr) * 2013-12-24 2015-07-02 University Of Florida Research Foundation, Inc. Dérivés de phénazine comme agents antimicrobiens

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080139545A1 (en) * 2006-05-22 2008-06-12 Won-Taek Choe Formulation to treat ear infection
WO2008043175A1 (fr) * 2006-10-13 2008-04-17 Kane Biotech Inc. COMPOSITIONS D'ANTIBIOFILMS À BASE DE b-N-ACÉTYLGLUCOSAMINIDASE SOLUBLE ET LEURS UTILISATIONS
US20090238923A1 (en) * 2007-11-05 2009-09-24 Danisco Us Inc., Genencor Division Variants of bacillus licheniformis alpha-amylase with increased thermostability and/or decreased calcium dependence
US20110086101A1 (en) * 2008-04-03 2011-04-14 Srinivasa Madhyastha Dispersinb, 5-Fluorouracil, Deoxyribonuclease I and Proteinase K-Based Antibiofilm Compositions and Uses Thereof
US20110054026A1 (en) * 2008-05-22 2011-03-03 Michael Patrick Doyle Antimicrobial composition and use
US20130052250A1 (en) * 2010-02-12 2013-02-28 University Of Newcastle Upon Tyne Compounds and methods for biofilm disruption and prevention
US20150118219A1 (en) * 2012-05-11 2015-04-30 Smith & Nephew, Inc. Use of seaprose to remove bacterial biofilm
WO2015100331A2 (fr) * 2013-12-24 2015-07-02 University Of Florida Research Foundation, Inc. Dérivés de phénazine comme agents antimicrobiens

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110623060A (zh) * 2019-10-31 2019-12-31 福州大学 一种蛋白酶k在鲜鱼制品保鲜中的应用

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