title: Biological characterization of the hygrobafilomycin antibiotic JBIR-100 and bioinformatic insights into the hygrolide family of natural products.
abstract: The hygrolides, a family of 16-member-ring-containing plecomacrolides produced by Actinobacteria, exhibit numerous reported bioactivities. Using HR-MS/MS, nucleophilic 1,4-addition-based labeling, NMR, and bioinformatic analysis, we identified Streptomyces varsoviensis as a novel producer of JBIR-100, a fumarate-containing hygrolide, and elucidated the previously unknown stereochemistry of the natural product. We investigated the antimicrobial activity of JBIR-100, with preliminary insight into mode of action indicating that it perturbs the membrane of Bacillus subtilis. S. varsoviensis is known to produce compounds from multiple hygrolide sub-families, namely hygrobafilomycins (JBIR-100 and hygrobafilomycin) and bafilomycins (bafilomycin C1and D). In light of this, we identified the biosynthetic gene cluster for JBIR-100, which, to our knowledge, represents the first reported for a hygrobafilomycin. Finally, we performed a bioinformatic analysis of the hygrolide family, describing clusters from known and predicted producers. Our results indicate that potential remains for the Actinobacteria to yield novel hygrolide congeners, perhaps with differing biological activities.
authors.affiliation: Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA. Electronic address: emolloy@illinois.edu.
authors.forename: Evelyn M
authors.initials: EM
authors.lastname: Molloy
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA. Electronic address: tietz2@illinois.edu.
authors.forename: Jonathan I
authors.initials: JI
authors.lastname: Tietz
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA. Electronic address: pmblair2@illinois.edu.
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Blair
authors.affiliation: Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA. Electronic address: douglasm@illinois.edu.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Mitchell
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects / Q000254:growth & development; D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology*; D019295:Computational Biology; D004305:Dose-Response Relationship, Drug; D005658:Fungi / Q000187:drug effects / Q000254:growth & development; D018942:Macrolides / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D001688:Biological Products; C553372:JBIR-100; D018942:Macrolides
keywords: Antifungal; Antimicrobial; Bioinformatics; Hygrobafilomycin; Hygrolide; JBIR-100; Nucleophilic 1,4-addition; Plecomacrolide; Polyketide; Resistance mapping; Streptomyces varsoviensis; TS155-2; Whole-genome sequencing