Antimicrobial peptides and methods of using the same
Inventors
Jaynes, Jesse • Clemens, L. Edward • Lopez, Henry Willfred • Martin, George R. • Woodburn, Kathryn
Assignees
Publication Number
US-10548944-B1
Publication Date
2020-02-04
Expiration Date
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Abstract
Aspects of the present invention relate to peptides having antimicrobial activity. In certain aspects, the invention relates to peptides having potent antimicrobial activity, broad-spectrum antimicrobial activity, and/or the ability to kill otherwise antibiotic-resistant microbes, or microbes protected by biofilms.
Core Innovation
Aspects of the present invention relate to peptides having antimicrobial activity. The invention provides antimicrobial peptides and methods of using the same, and the peptides of this disclosure can have anti-bacterial, anti-fungal, and/or anti-protozoal activity. The peptides can kill microbial strains that are resistant to conventional antibiotics, and this disclosure provides antimicrobial peptides that are capable of killing microbes (e.g., bacteria) growing as a microbial biofilm.
Antibiotic resistance is a major health problem attributed in part to the widespread use of antibiotics and has created a powerful selection bias toward antibiotic resistant bacteria. Biofilms constitute a physical barrier to antibiotic exposure and are 20-1000 times more resistant to antibiotics than their planktonic counterparts, forming on tissues and medical implants where they can cause systemic infections. There is an urgent need for materials that are active against antibiotic resistant organisms in both free and biofilm form, and the technology described represents the first description of particular types of antimicrobial peptides that can be used a variety of applications to selectively kill microbes for purposes of treatment of conditions related to microbial infections.
Claims Coverage
Three inventive features are identified from the independent claims.
Antimicrobial peptide comprising specified RP sequences
An antimicrobial peptide, comprising a peptide sequence selected from: FIOKFAKOFKOFIOKFAKFAFAF (RP551, SEQ ID NO: 2); FAFAFKAFKKAFKOFOOAFOOAF (RP552, SEQ ID NO: 3); FOIKARFOVRARLOLKI (RP553, SEQ ID NO: 4); FRLKIKARLKVKIRFKL (RP554, SEQ ID NO: 5); FOLOAOIOVOLOAOIOL (RP555, SEQ ID NO: 6); FOLOAOIKVKLOAOIOL (RP556, SEQ ID NO: 7); RFCWKVCYKGICFKKCK (RP557, SEQ ID NO: 8); OWCFOVCYOGICYOOCO (RP559, SEQ ID NO: 10); OFCWOVCYOGICFOOCO (RP561, SEQ ID NO: 12); OCOOFCIGOYCVOWCFO (RP562, SEQ ID NO: 13); FOIOAOLOGGCLGOFCGGOIOAOLOF (RP565, SEQ ID NO: 16); FOIKAOLGGCLGKFCGGIKAOLKF (RP566, SEQ ID NO: 17); and FOIKAOLKGGCLGKFCGGKIKAOLKF (RP567, SEQ ID NO: 18).
Antimicrobial peptide with sequence variants or high identity to specified sequences
An antimicrobial peptide comprising: a peptide sequence selected from specific sequences (e.g., SEQ ID NO: 2, 4-8, 10, 12, 13 and 18); or a sequence having five or less amino acid substitutions relative to the specified sequence, wherein the five or less amino acid substitutions consist of substitution of a cationic amino acid of the sequence with an alternative cationic amino acid residue; or a peptide sequence having at least 90% sequence identity with a specified sequence.
Antimicrobial peptide comprising RP560 sequence
An antimicrobial peptide, comprising the sequence RWCFKVCYKGICYKKCK (RP560) (SEQ ID NO: 11).
The independent claims cover antimicrobial peptides defined by specified RP peptide sequences, peptides with limited cationic substitutions or high sequence identity to those sequences, and an antimicrobial peptide comprising the RP560 sequence.
Stated Advantages
Potent antimicrobial activity against bacteria, fungi, and protozoa as stated in the abstract and summary.
Broad-spectrum antimicrobial activity including activity against gram-negative and gram-positive organisms and fungal strains as described in the summary and examples.
Ability to kill microbes that are resistant to conventional antibiotics, including antibiotic-resistant bacterial strains as stated in the abstract and summary.
Capability to kill microbes growing as a microbial biofilm and to prevent or treat biofilms as described in the summary and examples.
Reduced risk of development of pathogen resistance relative to some conventional antibiotics as described in the examples (pathogens did not develop resistance to RP557 after serial passage).
Lack of cytotoxicity to mammalian cells in vitro for exemplary peptide RP557 as shown in the examples.
Favorable physicochemical stability for exemplary RP557: hydrophilic, highly soluble, stable at extremes of pH (<4), resistant to proteases and stable in serum as stated in the detailed description and examples.
Documented Applications
Treatment and prevention of microbial infections in subjects, including humans and animals, by administering a therapeutically effective amount of a subject peptide.
Topical application to wounds and burns, including use in an infected porcine burn model to reduce polymicrobial infection as documented in the examples.
Ophthalmic applications, including formulations for eye drops, ointments, gels, hydrophilic hydrogel contact lenses, and ocular polymer inserts for topical application to treat ocular infections such as bacterial keratitis as described in the compositions section.
Use as an antimicrobial preservative, disinfectant or sterile storage medium for ocular devices such as contact lenses and intraocular lens implants, and for storing/soaking/rinsing contact lenses as described in the compositions section.
Coating of medical devices, including implantable medical devices and indwelling devices (e.g., catheters, prosthetic joints, pacemakers) to prevent infection as described in the compositions and methods sections.
Inhalation administration for pulmonary delivery, including aerosolized liposomal formulations for delivery to the lungs as described in the compositions section.
Treatment of vulvovaginal candidiasis, as shown by topical RP557 efficacy in a rodent vaginal candidiasis model in the examples.
Treatment of acute bacterial skin and skin structure infections (ABSSSI) and infections caused by gram-negative pathogens and multidrug-resistant gram-positive bacteria (e.g., MRSA) as referenced in the introduction and methods.
Use in combination with conventional antibiotics or other therapeutic agents to treat or prevent infections and to reduce symptoms of microbial infections as described in the methods.
Use as research tools for identification and testing of candidate compounds, in vitro assays, potency assays, and competitive inhibition assays as described in the methods and definitions.
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