Self-derived structure-disrupting peptides targeting methionine aminopeptidase in pathogenic bacteria: a new strategy to generate antimicrobial peptides

Bacterial infection is one of the leading causes of death in young, elderly, and immune-compromised patients.The rapid spread ofmulti-drug-resistant (MDR) bacteria is a global health emergency and there is a lack of newdrugs to controlMDRpathogens.Wedescribe aheretofore-unexploreddiscoverypathway fornovel antibiotics that is based on self-targeting, structure-disrupting peptides. We show that a helical peptide, KFF-EcH3, derived from the Escherichia coli methionine aminopeptidase can disrupt secondary and tertiary structure of this essential enzyme, thereby killing the bacterium (includingMDR strains). Significantly, no detectable resistance developed against this peptide.Basedon a computational analysis, our study predictedthatpeptide KFF-EcH3has the strongest interaction with the structural core of the methionine aminopeptidase. We further used our approach to identify peptide KFF-NgH1 to target the same enzyme from Neisseria gonorrhoeae. This peptide inhibited bacterial growth and was able to treat a gonococcal infection in a human cervical epithelial cell model. These findings present an exciting new paradigm in antibiotic discovery using self-derived peptides that can be developed to target the structures of any essential bacterial proteins.