Antimicrobial peptides
Inventors
BACHNOFF, Niv • COHEN-KUTNER, Moshe
Assignees
Publication Number
US-10308693-B2
Publication Date
2019-06-04
Expiration Date
2036-02-17
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Abstract
The invention provides a peptide comprising: a core amino acid sequence, which is identical or similar to the amino acid sequence of a member of the Cecropin family. The invention further provides a nucleic acid sequence encoding the peptide and a vector comprising said nucleic acid. The invention further provides a pharmaceutical composition comprising said peptide or said nucleic acid.The invention further provides methods of treating an infection, overcoming inherent or acquired resistance of a microorganism to an antibiotic agent or disinfecting a wound, the methods comprises administering the peptide to a subject in need thereof.
Core Innovation
The invention provides peptides comprising a core amino acid sequence identical or similar to members of the Cecropin family, which are known potent antibacterial agents primarily from insects. These peptides are modified by extending the core sequence at the N-terminus and/or C-terminus by groups capable of forming covalent bonds, resulting in cyclic peptides or homomultimer assemblies with intermolecular covalent linkage. This conformation increases the stability of the peptides under oxidative conditions common in infections while retaining their original antimicrobial activity.
The problem being addressed is the widespread emergence of microorganisms resistant to currently available antimicrobial drugs, partly due to extensive use leading to resistant strains. Native Cecropins, although effective against a range of bacteria, are unstable and prone to degradation by host proteases, limiting their practical therapeutic application. The invention seeks to provide novel, stable peptide-based antibiotics resistant to proteolytic degradation, overcoming limitations in stability and efficacy of natural antimicrobial peptides, especially Cecropins.
The peptides of the invention are engineered to include cysteine residues at their termini, facilitating covalent linkage that forms cyclic or multimeric structures. Various embodiments allow different topologies and covalent bond types including disulfide bonds. Such structural modifications confer enhanced resistance to proteases like proteinase K, confirmed by experiments where native Cecropin A degrades rapidly while modified peptides remain intact and active. The peptides demonstrate strong bactericidal activity, including against drug-resistant strains, without cytotoxic effects on human cells.
Claims Coverage
The patent includes one independent claim focusing on a cyclic peptide with high sequence identity to a specified Cecropin-derived sequence, along with dependent claims covering pharmaceutical compositions and therapeutic methods. The inventive features described focus on peptide sequence identity, cyclic structure, pharmaceutical formulation, and specific therapeutic applications against gram negative bacteria and resistant strains.
Cyclic peptide with high sequence identity to SEQ ID NO: 6
A cyclic peptide having an amino acid sequence with at least 95% (or 99%) sequence identity to SEQ ID NO: 6, as specifically set forth in the claims.
Pharmaceutical composition comprising the cyclic peptide
A pharmaceutical composition comprising the cyclic peptide described, formatted as a liquid, cream, gel, paste, powder, emulsion, ointment, liniment, lotion, transdermal system, injection fluid, suspension, film patch, spray, capsule, or tablet.
Method of treating bacterial infection caused by gram negative bacteria
A method comprising administering the cyclic peptide to a subject in need to treat bacterial infection caused specifically by gram negative bacteria.
Method of overcoming antibiotic resistance in gram negative bacteria
A method including contacting gram negative bacteria, including Enterobacteriaceae, Pseudomonas, Salmonella, or Acinetobacter species, with the cyclic peptide to overcome inherent or acquired antibiotic resistance.
Method of disinfecting a cutaneous abscess with the cyclic peptide
A method utilizing the cyclic peptide to disinfect a cutaneous abscess infected by gram negative bacteria.
The claims cover a cyclic peptide highly similar to a Cecropin-derived sequence with stability and enhanced antimicrobial properties, compositions containing these peptides in various pharmaceutical forms, and their use in treating and disinfecting infections caused by gram negative and resistant bacteria.
Stated Advantages
The engineered peptides exhibit enhanced stability against proteolytic degradation, retaining antimicrobial activity where native Cecropins rapidly lose efficacy.
The peptides are potent bactericidal agents effective against a broad range of gram negative and resistant bacteria, including multi-drug resistant strains.
The peptides selectively target bacterial membranes causing physical disruption and bacterial death, with no observed cytotoxic effects on human cells such as HEK293 and primary erythrocytes.
The invention enables large-scale production of stable antimicrobial peptides suitable for pharmaceutical use.
The cyclic form of the peptides enhances stability without compromising biological activity, enabling therapeutic efficacy in vivo demonstrated by reduction in bacterial burden and abscess size in mouse infection models.
Documented Applications
Treatment of bacterial infections, including those caused by gram negative bacteria and antibiotic-resistant strains such as Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella Typhi, and Acinetobacter baumannii.
Pharmaceutical applications in forms such as liquids, creams, gels, powders, ointments, injections, patches, capsules, and tablets.
Methods of disinfecting wounds including blister wounds, soft tissue wounds, cutaneous abscesses, surgical wounds, lacerations, burns (partial or full thickness), ulcers (decubitus, stasis, leg, foot, venous, diabetic, ischemic, pressure), oral infections, and periodontal disease.
Use as agents to overcome inherent or acquired antibiotic resistance in microorganisms.
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