Structure, Bioactivity, and Resistance Mechanism of Streptomonomicin, an Unusual Lasso Peptide from an Understudied Halophilic Actinomycete. Issue 2 (19th February 2015)

• Record Type: Journal Article
• Authors: Metelev, Mikhail; Tietz, Jonathan I.; Melby, Joel O.; Blair, Patricia M.; Zhu, Lingyang; Livnat, Itamar; Severinov, Konstantin; Mitchell, Douglas A.
• Is Part Of: Chemistry & biology. Volume 22:Issue 2(2015)
• Page Start: 241
• Page End: 250
• Publication Date: 2015-02-19
• Subjects: Biochemistry -- Periodicals; 540
• DOI: 10.1016/j.chembiol.2014.11.017
• Languages: English
• ISSNs: 1074-5521

Abstract

Summary: 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. Graphical Abstract: Highlights: Streptomonomicin (STM) is a lasso peptide with a unique Ser1-Asp9 linkage STM exhibits activity against Gram-positive bacteria Substitutions in the essential two-component regulator WalR endow STM resistance Genome sequencing shows biosynthetic potential in the genus Streptomonospora Abstract : Metelev et al. report on a natural product, a lasso peptide antibiotic, from the understudied halophilic actinomycete genus Streptomonospora and demonstrate its biological activity and walR -mediated resistance mechanism. Furthermore, genome sequencing shows the natural product's biosynthetic origin and reveals the diverse biosynthetic ability of the genus.