WO2008033119A1 - Nouvelles combinaisons d'inhibiteurs de dnak avec des agents antibactériens connus - Google Patents

Nouvelles combinaisons d'inhibiteurs de dnak avec des agents antibactériens connus Download PDF

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Publication number
WO2008033119A1
WO2008033119A1 PCT/US2006/035272 US2006035272W WO2008033119A1 WO 2008033119 A1 WO2008033119 A1 WO 2008033119A1 US 2006035272 W US2006035272 W US 2006035272W WO 2008033119 A1 WO2008033119 A1 WO 2008033119A1
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WO
WIPO (PCT)
Prior art keywords
group
pro
antibacterial agent
known antibacterial
kit
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Application number
PCT/US2006/035272
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English (en)
Inventor
Michael Alan Sturgess
Kenneth E. Kovan
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Chaperone Technologies, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Chaperone Technologies, Inc. filed Critical Chaperone Technologies, Inc.
Priority to PCT/US2006/035272 priority Critical patent/WO2008033119A1/fr
Priority to EP06824922A priority patent/EP2076126A4/fr
Publication of WO2008033119A1 publication Critical patent/WO2008033119A1/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
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates generally to DnaK inhibiting agents. More specifically, the invention relates to natural peptide DnaK inhibitors, and analogs thereof, in combination with known antibacterial agents to elicit an enhanced inhibitory effect upon bacterial growth and/or bacteriocidal activity.
  • Two such peptides are drosocin, a 19 amino acid residue peptide from Drosophila (Bulet et al . , J “ . Biol. Chem. 268:14893-14897 (1993)) and pyrrhocoricin, a 20 amino acid residue peptide from Pyrrhocoris (Cociancich et al, Biochem. J. 300:567-575 (1994) ) .
  • Drosocin and pyrrhocoricin are glycopeptides characterized by the presence of a disaccharide in the mid- chain position. The presence of the disaccharide increases the in vitro antibacterial activity of drosocin, but decreases the activity of pyrrhocoricin (Bulet et al . , supra; Hoffmann et al . , Biochim. Biophys. Acta, 1426:459-467 (1999) ) . While active in vitro, both drosocin and pyrrhocoricin are known to be highly susceptible to proteolytic degradation in the presence of mammalian serum. Both aminopeptidase and carboxypeptidase cleavage products are observed. Metabolites lacking as few as five amino terminal or two carboxy terminal amino acids have been shown to be inactive as antibacterial agents in vitro (Bulet et al . , supra; Hoffmann et al . , supra) .
  • DnaK has been demonstrated to be the central protein in a multiprotein bacterial chaperone system including the chaperone protein DnaK and a variety of co-chaperone proteins such as DnaJ and GrpE.
  • the co-chaperone proteins are essential to the efficient physiological processing of both natural and unnatural substrates.
  • One role for this chaperone system is to catalyze the refolding of either unfolded or misfolded bacterial proteins, as is evident from the role of this system in the heat-shock response.
  • An additional role of the DnaK chaperone system is the regulation of gene expression through the processing of specific RNA polymerase subunits.
  • DnaK deletion mutants of many organisms have been generated and overall the mutant strains have been shown to exhibit lower growth rates, greater susceptibility to environmental stress, reduced viability in cellular environments, and reduced ability to establish infections in vivo compared to the wild-type strains.
  • DnaK chaperone system in bacterial growth and survival is only now starting to be appreciated and understood, the role and utility of DnaK inhibitors as antibacterial agents is not well established. Accordingly, there is a need to investigate and exploit the useful therapeutic activities of DnaK inhibitors, including pyrrhocoricin, drosocin and their analogs.
  • compositions, methods, and kits for inhibiting the growth of bacteria comprising a DnaK inhibitor and a known antibacterial agent.
  • coadministration of such agents enhances the antibacterial potential of the DnaK inhibitor, the known antibacterial agent, or both.
  • Such coadministration to patients suffering from a bacterial infection has the possible benefit of i) lowering the necessary therapeutically effective dose; ii) extending the duration of activity of a fixed dose,- iii) reducing the likelihood of the development of resistant strains of the infecting organism; and/or iv) expanding the spectrum of activity of the individual agents.
  • Agents that exhibit a therapeutic synergistic effect when coadministered are preferred.
  • one aspect of the present invention is directed to a method for treating a bacterial infection comprising coadministering to a patient in need of such treatment
  • the DnaK inhibitor is pyrrhocoricin, drosocin or an analog thereof, while the known antibacterial agent is an antibiotic from the fluoroquinolone, ⁇ -lactam, tetracycline, macrolide, aminoglycoside, glycopeptide, or folic acid synthesis inhibitor family of antibiotics.
  • the DnaK inhibitor and antibiotic provide a therapeutic synergistic effect .
  • Another aspect of the present invention is directed to a pharmaceutical composition for treating a bacterial infection, comprising:
  • the kit further comprises other apparatus and media for administering the agents to a patient, as well as instructions for using the kit to treat a bacterial infection.
  • FIG. 1 shows the structure of CHP-105, a typical peptide inhibitor of E. coli DnaK.
  • FIG. 4 shows the enhanced rate of antibacterial activity of a combination of 64 ⁇ g/ml CHP-105 and levofloxacin or gentamicin when administered to rapidly growing E. coli.
  • FIG. 5 shows the enhanced rate of antibacterial activity of a combination of 128 ⁇ g/ml CHP-105 and levofloxacin or gentamicin when administered to rapidly growing E. coli.
  • FIG. 6 shows the enhanced rate of antibacterial activity of a combination of 246 ⁇ g/ml CHP-105 and levofloxacin or gentamicin when administered to rapidly growing E. coli.
  • coadministration refers to the administration of a therapeutically effective amount of a first active agent (e.g., a DnaK inhibitor) and a therapeutically effective amount of a second active agent (e.g., a known antibacterial agent) to a patient.
  • Coadministration encompasses administration of the first and second agents in an essentially simultaneous manner, such as in a single pharmaceutical composition, for example, capsule or tablet having a fixed ratio of first and second amounts, or in multiple, separate capsules or tablets for each.
  • coadministration also encompasses use of each agent in a sequential manner in either order. When coadministration involves the separate administration of each agent, the agents are administered sufficiently close in time to have the desired therapeutic effect.
  • alkyl refers to a saturated aliphatic radical containing from one to ten carbon atoms or a mono- or polyunsaturated aliphatic hydrocarbon radical containing from two to twelve carbon atoms, the mono- or polyunsaturated aliphatic hydrocarbon radical containing at least one double or triple bond, respectively.
  • Alkyl refers to both branched and unbranched alkyl groups . Examples of alkyl include alkyl groups which are straight chain alkyl groups containing from one to eight carbon atoms and branched alkyl groups containing from three to eight carbon atoms.
  • alkyl groups which are straight chain alkyl groups containing from one to six carbon atoms and branched alkyl groups containing from three to six carbon atoms. It is understood that any combination term using an "alk” or “alkyl” prefix refers to analogs according to the above definition of "alkyl”. For example, terms such as “alkoxy” and “alkythio” refer to alkyl groups linked to a second group via an oxygen or sulfur atom.
  • aroyl means an aryl-C(O)— group in which the aryl group is as previously described. The bond to the parent moiety is through the carbonyl .
  • acetyl refers to CH 3 C(O)-.
  • R 1 adds a net positive charge to the N-terminus of said peptide and is selected from the group consisting of (a) a straight chain, branched, cyclic or heterocyclic alkyl group,- (b) a straight chain, branched, cyclic or heterocyclic alkanoyl group,-
  • R 2 is selected from the group consisting of
  • antibiotics examples include, e.g., linezolid, amikacin, gentamicin, tobramycin, imipenem, meropenem, cefotetan, cefoxitin, cefuroxime, cefoperazone, cefotaxime, ceftazidime, ceftozoxime, ceftriaxone, cefepime, azithromycin, ampicillin, mezlocillin, piperacillin, ticarcillin, ciprofloxacin, levofloxacin, alatrofloxacin, gatifloxacin, minocycline, chloramphenicol, clindamycin, vancomycin, cefazolin, penicillin G, nafcillin, ofloxacin, and oxacillin.
  • the particular antibiotic chosen may depend on the specific bacterial infection presented to the clinician.
  • prodrug refers to a derivative of a drug molecule that requires a chemical or enzymatic biotransformation in order to release the active parent drug in the body.
  • all stereoisomers for example, geometric isomers, optical isomers and the like
  • the agents described above including those of salts and solvates
  • enantiomeric forms which may exist even in the absence of asymmetric carbons
  • rotameric forms atropisomers, and diastereomeric forms
  • the actual dosages of the DnaK inhibitor and the known antibacterial agent employed in the treatment may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art.
  • the amount and frequency of administration of the DnaK inhibitor and the known antibacterial agent will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated.
  • the DnaK inhibitor and the known antibacterial agent can be administered orally, parenterally, topically, rectally, or intranasally, either substantially simultaneously or sequentially.
  • Preferred routes of administration are oral and intravenous administration.
  • Each of the agents can be administered by the same route (e.g., injection), either in a single dosage form or as separate dosage forms, or by separate routes (e.g., orally and parenterally) .
  • Parenteral administrations include injections to generate a systemic effect or injections directly to the afflicted area.
  • parenteral administrations are subcutaneous, intravenous, intramuscular, intradermal, intrathecal, intraocular, intravetricular, and general infusion techniques.
  • compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers including, e.g., excipients and auxiliaries that facilitate processing of the active agents into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • agents can be formulated by combining active compounds with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the agents to be formulated as tablets, pills, lozenges, dragees, capsules, liquids, solutions, emulsions, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient.
  • a carrier can be at least one substance that may also function, for example, as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, tablet disintegrating agent, or encapsulating agent.
  • Such carriers or excipients include, e.g., magnesium carbonate, magnesium stearate, talc, sugar, lactose, sucrose, pectin, dextrin, mannitol, sorbitol, starches, gelatin, cellulosic materials, low melting wax, cocoa butter or powder, polymers such as polyethylene glycols, and other pharmaceutical acceptable materials.
  • Sterile injectable solutions can be prepared by incorporating the active agent or agents in the required amount in the appropriate solvent with optional ingredients as required (e.g., as enumerated above), followed by, for example, filter sterilization.
  • optional ingredients e.g., as enumerated above
  • filter sterilization e.g., filter sterilization.
  • preferred methods of preparation include, for example, vacuum drying and freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions .
  • parenteral administrations also include aqueous solutions of a water-soluble form, such as, without limitation, a salt, of the active agent or agents.
  • suspensions of the active agents may be prepared in a lipophilic vehicle.
  • Suitable lipophilic vehicles include, for example, fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate and triglycerides, and materials such as liposomes.
  • Aqueous injection suspensions preferably contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers and/or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • a pharmaceutical composition may be formulated in a suitable ointment containing the active agents suspended or dissolved in one or more carriers.
  • Carriers for topical administration of the agents include, e.g., mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax, and water.
  • the pharmaceutical compositions can be formulated in suitable lotions, including, for example, suspensions, emulsions, and creams containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Suitable carriers include, e.g., mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, ceteary alcohol, 2- octyldodecanol, benzyl alcohol, and water.
  • agents may also be formulated as depot preparations .
  • Such long acting formulations may be in the form of implants.
  • Agents may be formulated for this route of administration with suitable polymers, hydrophobic materials, or as a sparing soluble derivative such as, without limitation, a sparingly soluble salt.
  • DnaK inhibitor CHP-105 structure shown in FIG. 1 obtained from Chaperone Technologies, Inc. (Philadelphia, PA) at concentrations of 16 ⁇ g/ml (0.25 x MIC; FIG. 2), 32 ⁇ g/ml (0.5 x MIC; FIG. 3), 64 ⁇ g/ml (1 x MIC; FIG. 4), 128 ⁇ g/ml (2 x MIC; FIG. 5) and 256 ⁇ g/ml (4 x MIC; FIG.
  • the combinations of 128 ⁇ g/ml CHP-105 with levofloxacin produced an additive decrease of 1.41 CFU at 12 hrs and a synergistic decrease of 4.59 CFU at 24 hrs, respectively, compared to the most active single agent (FIG. 5) .
  • the combination of 128 ⁇ g/ml CHP-105 with gentamicin produced synergistic decreases of 2.94 and 5.29 CFU at 12 and 24 hrs, respectively, compared to the most active single agent (FIG. 5) .
  • CHP-105 in concentrations 0.25 x MIC and 0.50 x MIC was applied to midlogarithmic phase bacterial culture either alone (results not shown) or in combination with 0.25 x MIC levofloxacin. As in analysis above, untreated bacterial culture served as growth control.

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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des compositions, des procédés et des coffrets comportant (a) une quantité thérapeutique efficace d'un inhibiteur de DnaK ; et (b) une quantité thérapeutique efficace d'un agent antibactérien connu. De tels compositions, procédés et coffrets sont utiles dans le traitement de diverses infections bactériennes.
PCT/US2006/035272 2006-09-12 2006-09-12 Nouvelles combinaisons d'inhibiteurs de dnak avec des agents antibactériens connus WO2008033119A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/US2006/035272 WO2008033119A1 (fr) 2006-09-12 2006-09-12 Nouvelles combinaisons d'inhibiteurs de dnak avec des agents antibactériens connus
EP06824922A EP2076126A4 (fr) 2006-09-12 2006-09-12 Nouvelles combinaisons d'inhibiteurs de dnak avec des agents antibactériens connus

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Application Number Priority Date Filing Date Title
PCT/US2006/035272 WO2008033119A1 (fr) 2006-09-12 2006-09-12 Nouvelles combinaisons d'inhibiteurs de dnak avec des agents antibactériens connus

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WO2008033119A1 true WO2008033119A1 (fr) 2008-03-20

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020035061A1 (en) * 1996-08-21 2002-03-21 Timothy J. Krieger Compositions and methods for treating infections using cationic peptides alone or in combination with antibiotics
WO2006052129A2 (fr) * 2004-11-10 2006-05-18 Nederlandse Organisatie Voor Toegepast-Natuurwetenschappelijk Onderzoek Tno Antibiotiques ameliores

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1194548A4 (fr) * 1999-06-23 2003-06-18 Wistar Inst Nouveaux peptides derives de pyrrhocoricine et leurs procedes de mise en application
US20030108957A1 (en) * 2002-07-19 2003-06-12 The Wistar Institute Of Anatomy And Biology Biocidal molecules, macromolecular targets and methods of production and use

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020035061A1 (en) * 1996-08-21 2002-03-21 Timothy J. Krieger Compositions and methods for treating infections using cationic peptides alone or in combination with antibiotics
WO2006052129A2 (fr) * 2004-11-10 2006-05-18 Nederlandse Organisatie Voor Toegepast-Natuurwetenschappelijk Onderzoek Tno Antibiotiques ameliores

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KRAGOL G.: "Identification of Crucial Residues for the Antibacterial Activity of the Proline-Rich Peptide, Pyrrhocoricin", EUR. J. BIOCHEM., vol. 269, 2002, pages 4226 - 4237, XP008106140 *
See also references of EP2076126A4 *

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EP2076126A1 (fr) 2009-07-08
EP2076126A4 (fr) 2011-12-28

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