title: Metabolomics-Driven Discovery of a Prenylated Isatin Antibiotic Produced by Streptomyces Species MBT28.
abstract: Actinomycetes are a major source of antimicrobials, anticancer compounds, and other medically important products, and their genomes harbor extensive biosynthetic potential. Major challenges in the screening of these microorganisms are to activate the expression of cryptic biosynthetic gene clusters and the development of technologies for efficient dereplication of known molecules. Here we report the identification of a previously unidentified isatin-type antibiotic produced by Streptomyces sp. MBT28, following a strategy based on NMR-based metabolomics combined with the introduction of streptomycin resistance in the producer strain. NMR-guided isolation by tracking the target proton signal resulted in the characterization of 7-prenylisatin (1) with antimicrobial activity against Bacillus subtilis. The metabolite-guided genome mining of Streptomyces sp. MBT28 combined with proteomics identified a gene cluster with an indole prenyltransferase that catalyzes the conversion of tryptophan into 7-prenylisatin. This study underlines the applicability of NMR-based metabolomics in facilitating the discovery of novel antibiotics.
authors.forename: Changsheng
authors.initials: C
authors.lastname: Wu
authors.forename: Chao
authors.initials: C
authors.lastname: Du
authors.affiliation: Leiden Institute of Chemistry, Leiden University , Einsteinweg 55, 2333 CC Leiden, The Netherlands.
authors.forename: Jacob
authors.initials: J
authors.lastname: Gubbens
authors.forename: Young Hae
authors.initials: YH
authors.lastname: Choi
authors.forename: Gilles P
authors.initials: GP
authors.lastname: van Wezel
mesh_terms: D039903:Actinobacteria / Q000235:genetics; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D001412:Bacillus subtilis / Q000187:drug effects; D004122:Dimethylallyltranstransferase / Q000378:metabolism; D024881:Drug Resistance, Bacterial; D007510:Isatin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D055432:Metabolomics; D015394:Molecular Structure; D005810:Multigene Family; D019906:Nuclear Magnetic Resonance, Biomolecular; D016133:Polymerase Chain Reaction; D054876:Prenylation; D013302:Streptomyces / Q000737:chemistry* / Q000235:genetics; D014364:Tryptophan / Q000737:chemistry
chemical_list: C000604762:7-prenylisatin; D000900:Anti-Bacterial Agents; D007510:Isatin; D014364:Tryptophan; D004122:Dimethylallyltranstransferase