A Systematic Analysis of Biosynthetic Gene Clusters in the Human Microbiome Reveals a Common Family of Antibiotics

Mohamed S. Donia

Peter Cimermancic

Christopher J. Schulze

Laura C. Wieland Brown

DOI: http://dx.doi.org/10.1016/j.cell.2014.08.032

Highlights

•3,118 biosynthetic gene clusters were identified in the human microbiome
•All families, including complex polyketides and nonribosomal peptides, are present
•Thiopeptide antibiotic gene clusters are widespread among the human microbiota
•A previously unknown antibiotic, lactocillin, has been discovered from a vaginal commensal

Summary

In complex biological systems, small molecules often mediate microbe-microbe and microbe-host interactions. Using a systematic approach, we identified 3,118 small-molecule biosynthetic gene clusters (BGCs) in genomes of human-associated bacteria and studied their representation in 752 metagenomic samples from the NIH Human Microbiome Project. Remarkably, we discovered that BGCs for a class of antibiotics in clinical trials, thiopeptides, are widely distributed in genomes and metagenomes of the human microbiota. We purified and solved the structure of a thiopeptide antibiotic, lactocillin, from a prominent member of the vaginal microbiota. We demonstrate that lactocillin has potent antibacterial activity against a range of Gram-positive vaginal pathogens, and we show that lactocillin and other thiopeptide BGCs are expressed in vivo by analyzing human metatranscriptomic sequencing data. Our findings illustrate the widespread distribution of small-molecule-encoding BGCs in the human microbiome, and they demonstrate the bacterial production of drug-like molecules in humans.

Received: April 17, 2014; Received in revised form: May 30, 2014; Accepted: August 20, 2014;