Amycomicin is a potent and specific antibiotic discovered with a targeted interaction screen

Significance Bacteria, especially actinomycetes, produce the majority of our clinically useful small-molecule antibiotics. Genomic analyses of antibiotic-producing strains indicate that earlier discovery efforts revealed only a fraction of the likely antibiotic candidates. In an effort to uncover these previously missed candidates, we developed an approach that utilizes the ability of microbial communities to produce antibiotics that are not produced by any single member in isolation. Successful communities were established and deconvoluted to identify both producers and inducers of antibiotic activity. One inducer–producer pair made amycomicin, a potent and specific antibiotic againstStaphylococcus aureus , an important human pathogen. Amycomicin targets fatty acid biosynthesis and exhibits in vivo efficacy against antibiotic-resistant skin infections in a mouse model.