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Proc Natl Acad Sci U S A. 2018 Oct 2;115(40):10124-10129. doi: 10.1073/pnas.1807613115. Epub 2018 Sep 18.

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

Author information

1
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115.
2
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115.
3
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232.
4
School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo 14040-903, Brazil.
5
Genome Informatics Section, Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892.
6
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115; jon_clardy@hms.harvard.edu roberto_kolter@hms.harvard.edu.
7
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115; jon_clardy@hms.harvard.edu roberto_kolter@hms.harvard.edu.

Abstract

The 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 (AMY), a highly modified fatty acid containing an epoxide isonitrile warhead as a potent and specific inhibitor of Staphylococcus aureus Amycomicin targets an essential enzyme (FabH) in fatty acid biosynthesis and reduces S. aureus infection in a mouse skin-infection model. The discovery of AMY demonstrates the utility of screening complex communities against specific targets to discover small-molecule antibiotics.

KEYWORDS:

Staphylococcus aureus; actinomycete; antibiotic; fatty acid biosynthesis; interspecies interactions

PMID:
30228116
PMCID:
PMC6176635
DOI:
10.1073/pnas.1807613115
[Indexed for MEDLINE]
Free PMC Article

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