Science, Medicine, and the Anesthesiologist

Microbial resistance to antibiotics is an ever-present challenge in the management of infections and has traditionally been addressed by the reiterative synthesis of novel synthetic antibiotics. Antimicrobial peptide antibiotics are produced naturally by many microbial organisms and are an ancient form of host defense allowing microorganisms to compete for survival in their niche. Currently, a limited number of naturally occurring peptide antibiotics are in clinical use, including bacitracin, colistin, and polymyxin B. The human microbiome provides an untapped resource for identifying small peptides (less than 50 amino acids) with antimicrobial activities. The authors conducted a computational analysis of 1,773 previously assembled human metagenomes for small genetic open reading frames encoding small peptides. They identified 323 candidates with predicted antimicrobial properties predicted by software (AmPEP) based on distribution patterns of amino acid properties along the sequence. Seventy-eight of these peptide candidates were synthesized to test for toxicity against human cells and antibiotic activity in preclinical murine models of skin abscesses and deep thigh infections. More than half of the candidate peptides displayed antimicrobial activity at concentrations that were not toxic to human cells. Five of the most promising candidates were derived from diverse phyla from human oral, skin, and gut locations.