Structure determination and interception of biosynthetic intermediates for the plantazolicin class of highly discriminating antibiotics

Katie J. Molohon, Joel O. Melby, Jaeheon Lee, Bradley S. Evans, Kyle L. Dunbar, Stefanie B. Bumpus, Neil L. Kelleher, Douglas A. Mitchell*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

Abstract

The soil-dwelling, plant growth-promoting bacterium Bacillus amyloliquefaciens FZB42 is a prolific producer of complex natural products. Recently, a new FZB42 metabolite, plantazolicin (PZN), has been described as a member of the growing thiazole/ oxazole-modified microcin (TOMM) family. TOMMs are biosynthesized from inactive, ribosomal peptides and undergo a series of cyclodehydrations, dehydrogenations, and other modifications to become bioactive natural products. Using high-resolution mass spectrometry, chemoselective modification, genetic interruptions, and other spectroscopic tools, we have determined the molecular structure of PZN. In addition to two conjugated polyazole moieties, the amino-Terminus of PZN has been modified to Nα,Nα-dimethylarginine. PZN exhibited a highly selective antibiotic activity toward Bacillus anthracis, but no other tested human pathogen. By altering oxygenation levels during fermentation, PZN analogues were produced that bear variability in their heterocycle content, which yielded insight into the order of biosynthetic events. Lastly, genome-mining has revealed the existence of four additional PZN-like biosynthetic gene clusters. Given their structural uniqueness and intriguing antimicrobial specificity, the PZN class of antibiotics may hold pharmacological value.

Original languageEnglish (US)
Pages (from-to)1307-1313
Number of pages7
JournalACS chemical biology
Volume6
Issue number12
DOIs
StatePublished - Dec 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

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