Compositions and methods of use of synthetic peptides with Mycobacterium abscessus inhibitory activity
Inventors
Haydel, Shelley • Diehnelt, Chris
Assignees
Arizona State University ASU • Arizona State University Downtown Phoenix campus
Publication Number
US-11752195-B2
Publication Date
2023-09-12
Expiration Date
2042-04-15
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Abstract
Synthetic antimicrobial peptides, compositions comprising thereof, and methods of use for modulating one or more symptoms of an infection in a subject are disclosed. In some aspects, the infection is caused by mycobacteria, for example, a nontuberculous mycobacterium such as Mycobacterium abscessus. In other aspects, the infection is caused by Escherichia coli, Pseudomonas aeruginosa, or methicillin-resistant Staphylococcus aureus (MRSA). Also disclosed are methods of identifying synthetic antimicrobial peptides against a pathogen with no known effective treatment using a library of synthetic peptides.
Core Innovation
The invention discloses synthetic antimicrobial peptides, compositions containing these peptides, and methods for treating bacterial infections, particularly those caused by drug-resistant pathogens. The peptides, specifically ASU2001, ASU2009, ASU2019, ASU2056, ASU2059, and ASU2060, are designed to modulate one or more signs or symptoms of infection in a subject. These peptides exhibit activity against various bacteria, including Mycobacterium abscessus, Escherichia coli, Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus aureus (MRSA).
A core aspect of the disclosed technology is the development and use of high-throughput screening methods utilizing peptide microarrays. This approach enables rapid identification of synthetic antimicrobial peptides by generating a library of random peptides composed of L- and D-amino acid residues, physically displayed on a silicon wafer as a microarray. The method includes exposing fluorescently labeled bacteria to the array, identifying peptides that bind bacteria with high fluorescence, and selecting peptides that exhibit bacterial growth inhibition in vitro.
The problem addressed by this invention is the increasing prevalence of antibiotic-resistant bacterial infections and the lack of effective therapeutic options, particularly for infections such as Mycobacterium abscessus, for which there are currently no effective drug treatments. The development of synthetic antimicrobial peptides provides alternative therapeutic options to overcome existing resistance and provide effective treatment for challenging infections.
The invention also includes compositions that may combine the synthetic peptides with a metal ion chelator such as EDTA and, optionally, an antibiotic, to enhance antibacterial activity. The methods disclosed provide a systematic approach to identifying, characterizing, and applying synthetic antimicrobial peptides, especially for treating infections with limited conventional therapy options.
Claims Coverage
There are two independent claims, each encompassing distinct inventive features for compositions and methods involving synthetic antimicrobial peptides.
Antimicrobial composition comprising specific synthetic peptides
An antimicrobial composition comprising at least one peptide selected from the group consisting of: ASU2001 (SEQ ID NO: 1), ASU2009 (SEQ ID NO:2), ASU2019 (SEQ ID NO: 3), ASU2056 (SEQ ID NO: 4), ASU2059 (SEQ ID NO: 5), and ASU2060 (SEQ ID NO: 6). - The composition is defined by the inclusion of one or more of these specific synthetic peptides. - The composition may optionally include a chelator that sequesters metal ions. - The composition may further comprise an antibiotic.
Method of treating bacterial infection using specified synthetic peptides
A method of treating a bacterial infection in a subject comprising administering to the subject at least one peptide from the group consisting of: ASU2001 (SEQ ID NO: 1), ASU2009 (SEQ ID NO:2), ASU2019 (SEQ ID NO: 3), ASU2056 (SEQ ID NO: 4), ASU2059 (SEQ ID NO: 5), and ASU2060 (SEQ ID NO: 6). - The method includes use against infections caused by Escherichia coli, Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus (MRSA), or Mycobacterium abscessus. - For Mycobacterium abscessus infections, details are provided for treatment of both smooth and rough morphotypes using specific peptides (ASU2056 and ASU2060 for smooth, ASU2001 for rough), and may include co-administration of a chelator.
The inventive features cover both the compositions of specific synthetic antimicrobial peptides and methods for using these peptides to treat bacterial infections, particularly targeting challenging pathogens and morphotypes.
Stated Advantages
The peptides and compositions are effective against drug-resistant bacteria for which there are currently no effective treatments.
The high-throughput peptide microarray screening approach enables rapid discovery and characterization of active antimicrobial peptides.
Disclosed peptides demonstrate minimal toxicity, including low hemolytic activity against human red blood cells.
Certain peptides, such as ASU2060, retain antimicrobial activity after exposure to human serum, indicating stability.
The flexibility of peptide library synthesis allows for inclusion of D-amino acids, enhancing stability and diversity.
AMPs may be more potent and cause fewer side effects than traditional orally or intravenously administered antibiotics, especially when delivered as inhaled therapeutics.
Compositions can be optimized with a chelator and/or antibiotic to enhance effectiveness.
Documented Applications
Treatment of bacterial infections caused by Mycobacterium abscessus, Escherichia coli, Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus aureus (MRSA).
Treatment of drug-resistant mycobacterium infections, including those with smooth and rough morphotypes.
Treatment or prevention of infections such as toxic shock syndrome, meningitis, pneumonia, cellulitis, osteomyelitis, endocarditis, ulcers, burns, urinary tract infections, gastroenteritis, anthrax, syphilis, septicemia, Buruli ulcer, mycetoma, chromoblastomycosis, vaginal candidiasis, tuberculosis, otitis media, eczema, diabetic ulcers, toenail fungus, venous ulcers, infected burns, infected wounds, infected ballistic wounds, and plague.
Treatment of primary, secondary, and opportunistic infections associated with trauma, surgery, endotracheal intubation, tracheostomy, and cystic fibrosis.
Targeting gram-negative pathogens and multidrug-resistant gram-positive bacteria, including Acinetobacter baumannii and community-acquired MRSA.
Activity against fungal strains such as Candida albicans, Candida parapsilosis, Candida krusei, Aspergillus fumigatus, Aspergillus flavus, Absidia corymbifera, Fusarium solani, and Mucor.
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