Mining human microbiomes reveals an untapped source of peptide antibiotics

Drug-resistant bacteria are outpacing traditional antibiotic discovery efforts. Here, we computationally screened 444,054 previously reported putative small protein families from 1,773 human metagenomes for antimicrobial properties, identifying 323 candidates encoded in small open reading frames (smORFs). To test our computational predictions, 78 peptides were synthesized and screened for antimicrobial activity in vitro, with 70.5% displaying antimicrobial activity. As these compounds were different compared with previously reported antimicrobial peptides, we termed them smORF-encoded peptides (SEPs). SEPs killed bacteria by targeting their membrane, synergizing with each other, and modulating gut commensals,…

• BA
  Brain and Behavior Research Foundation
• PA
  Procter and Gamble
• UO
  University of Pennsylvania
• UT
  United Therapeutics Corporation
• AF
  ACE Foundation
• NI
  National Institutes of Health

  Awards: R01AI148623, R35GM138201
• DT
  Defense Threat Reduction Agency

  Awards: R01AI148623, HDTRA11810041, HDTRA1-23-1-0001, R01AI143757, HDTRA1-21-1-0014
• PS
  Perelman School of Medicine, University of Pennsylvania