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

doi:10.1021/cb200339d

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

Molecular Biosciences

Research output: Contribution to journal › Article › peer-review

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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 language	English (US)
Pages (from-to)	1307-1313
Number of pages	7
Journal	ACS chemical biology
Volume	6
Issue number	12
DOIs	https://doi.org/10.1021/cb200339d
State	Published - Dec 2011

Funding

We are grateful for the gift of B. amyloliquefaciens strains RSpMarA2 and RS33 from R. Borriss (Humboldt Universit€at Berlin, Germany). VRE strain U503 and S. aureus strain NRS-384/USA300 were kindly provided by J. Williams and P. Hergenrother (University of Illinois), and L. monocytogenes and B. anthracis Sterne were from J. Call (USDA-ARS) and S. Stibitz (FDA), respectively. T. Maxson, N. Ethridge, A. Mohan, and M. Sivaguru are acknowledged for their technical assistance. Members of the Mitchell lab assisted in the critical review of this manuscript. This work was supported by institutional funds provided by the University of Illinois (D.A.M.) and the NIH (GM 067193, N.L.K.). K.J.M. was supported in part by a Graduate College Fellowship (University of Illinois) and NIH Cellular and Molecular Biology Training Grant (T32 GM007-283). K.L.D. was supported by the NIH Training Program in Chemistry−Interface with Biology (T32 GM070421).

ASJC Scopus subject areas

Biochemistry
Molecular Medicine

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10.1021/cb200339d

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title = "Structure determination and interception of biosynthetic intermediates for the plantazolicin class of highly discriminating antibiotics",

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.",

author = "Molohon, {Katie J.} and Melby, {Joel O.} and Jaeheon Lee and Evans, {Bradley S.} and Dunbar, {Kyle L.} and Bumpus, {Stefanie B.} and Kelleher, {Neil L.} and Mitchell, {Douglas A.}",

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

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