title: A systematic analysis of biosynthetic gene clusters in the human microbiome reveals a common family of antibiotics.
abstract: 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. PAPERCLIP:
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and the California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Mohamed S
authors.initials: MS
authors.lastname: Donia
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and the California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Cimermancic
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Schulze
authors.affiliation: Department of Chemistry, Indiana University, Bloomington, IN 47405, USA.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Wieland Brown
authors.affiliation: The Genome Institute, Department of Medicine and Department of Genetics, Washington University School of Medicine, St. Louis, MO 63108, USA.
authors.forename: John
authors.initials: J
authors.lastname: Martin
authors.affiliation: The Genome Institute, Department of Medicine and Department of Genetics, Washington University School of Medicine, St. Louis, MO 63108, USA.
authors.forename: Makedonka
authors.initials: M
authors.lastname: Mitreva
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jon
authors.initials: J
authors.lastname: Clardy
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
authors.forename: Roger G
authors.initials: RG
authors.lastname: Linington
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and the California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: fischbach@fischbachgroup.org.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Fischbach
mesh_terms: D000595:Amino Acid Sequence; D001419:Bacteria / Q000737:chemistry* / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D053898:Biosynthetic Pathways; D041981:Gastrointestinal Tract / Q000382:microbiology; D006801:Humans; D056186:Metagenomics / Q000379:methods*; D064307:Microbiota; D008969:Molecular Sequence Data; D009055:Mouth / Q000382:microbiology; D005810:Multigene Family; D046908:Peptide Biosynthesis, Nucleic Acid-Independent; D061065:Polyketides / Q000032:analysis
chemical_list: D061065:Polyketides