Discovery of novel antimicrobials within microbiomes

Antimicrobial-resistant bacterial and fungal pathogens constitute a severe threat to public health. The pace at which new antimicrobials are being released is far slower than the pace of resistance emergence. Over the last decade, however, the genomics big data revolution has catalyzed major advances in antimicrobial discovery. Here, we briefly review how different human and other microbiomes have been mined to accurately extract biosynthetic gene clusters and antimicrobial peptides and proteins, with a focus on the latter groups. In addition to classical methods, artificial intelligence-enabled computational methods and innovative experimental strategies are increasingly used to prioritize candidates, identify novel small molecules and proteins active against priority pathogens, and reveal new modes of action. We highlight the urgent need to expand antifungal discovery, given the limited number of therapeutic classes and the slow pace of pipeline replenishment.