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

Abstract

AbstractThe rapid emergence of antibiotic-resistant pathogenic bacteria has accelerated the search for new antibiotics. Many clinically used antibacterials were discovered through culturing a single microbial species under nutrient-rich conditions, but in the environment, bacteria constantly encounter poor nutrient conditions and interact with neighboring microbial species. In an effort to recapitulate this environment we generated a nine-strain Actinomycete community and used 16S rDNA sequencing to deconvolute the stochastic production of antimicrobial activity that was not observed from any of the axenic cultures. We subsequently simplified the community to just two strains and identified Amycolatopsis sp. AA4 as the producing strain and Streptomyces coelicolor M145 as an inducing strain. Bioassay-guided isolation identified amycomicin, a highly modified fatty acid containing an epoxide isonitrile warhead as a potent and specific inhibitor of Staphylococcus aureus. Amycomicin targets an essential enzyme in fatty acid biosynthesis (FabH) and reduces S. aureus infection in a mouse skin infection model. The discovery of amycomicin demonstrates the utility of screening complex communities against specific targets to discover small-molecule antibiotics.SignificanceBacteria, especially actinomycetes, produce the majority of our clinically useful small-molecule antibiotics. Genomic analyses of antibiotic-producing strains indicate that earlier discovery efforts found 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 against Staphylococcus aureus, an important human pathogen. Amycomicin targets fatty acid biosynthesis and exhibits in vivo efficacy against skin infections in a mouse model.