title: Structure, bioactivity, and resistance mechanism of streptomonomicin, an unusual lasso Peptide from an understudied halophilic actinomycete.
abstract: Natural products are the most historically significant source of compounds for drug development. However, unacceptably high rates of compound rediscovery associated with large-scale screening of common microbial producers have resulted in the abandonment of many natural product drug discovery efforts, despite the increasing prevalence of clinically problematic antibiotic resistance. Screening of underexplored taxa represents one strategy to avoid rediscovery. Herein we report the discovery, isolation, and structural elucidation of streptomonomicin (STM), an antibiotic lasso peptide from Streptomonospora alba, and report the genome for its producing organism. STM-resistant clones of Bacillus anthracis harbor mutations to walR, the gene encoding a response regulator for the only known widely distributed and essential two-component signal transduction system in Firmicutes. To the best of our knowledge, Streptomonospora had been hitherto biosynthetically and genetically uncharacterized, with STM being the first reported compound from the genus. Our results demonstrate that understudied microbes remain fruitful reservoirs for the rapid discovery of novel, bioactive natural products.
authors.affiliation: Institute for Nanobiotechnologies, Saint Petersburg State Polytechnical University, Saint Petersburg 195251, Russia; Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Metelev
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
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; Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Joel O
authors.initials: JO
authors.lastname: Melby
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Blair
authors.affiliation: NMR Laboratory, School of Chemical Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Lingyang
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Itamar
authors.initials: I
authors.lastname: Livnat
authors.affiliation: Institute for Nanobiotechnologies, Saint Petersburg State Polytechnical University, Saint Petersburg 195251, Russia; Department of Molecular Biology and Biochemistry, Waksman Institute for Microbiology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Severinov
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Institute for Genomic Biology, 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: D039903:Actinobacteria / Q000235:genetics / Q000378:metabolism*; D000900:Anti-Bacterial Agents / Q000096:biosynthesis / Q000737:chemistry* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000096:biosynthesis / Q000737:chemistry* / Q000494:pharmacology; D016680:Genome, Bacterial; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D005810:Multigene Family; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000096:biosynthesis / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D017422:Sequence Analysis, DNA; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D010455:Peptides; D010456:Peptides, Cyclic; C000602703:streptomonomicin peptide, Streptomonospora alba