Structure, bioactivity, and resistance mechanism of streptomonomicin, an unusual lasso peptide from an understudied halophilic actinomycete

Mikhail Metelev, Jonathan I. Tietz, Joel O. Melby, Patricia M. Blair, Lingyang Zhu, Itamar Livnat, Konstantin Severinov, Douglas A. Mitchell

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)241-250
Number of pages10
JournalChemistry and Biology
Volume22
Issue number2
DOIs
StatePublished - Feb 19 2015

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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