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ACS Infect Dis. 2016 Mar 10;2(3):207-220. Epub 2015 Dec 23.

Plantazolicin is an ultra-narrow spectrum antibiotic that targets the Bacillus anthracis membrane.

Author information

1
Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801.
2
Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801.
3
Department of Physics and Center for the Physics of Living Cells, University of Illinois at Urbana-Champaign, Urbana, IL 61801.
4
Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801.
5
Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD 21702.
6
Department of Crop Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801.
7
Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801; Department of Physics and Center for the Physics of Living Cells, University of Illinois at Urbana-Champaign, Urbana, IL 61801; Howard Hughes Medical Institute, Chevy Chase, MD 20815.
8
Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801.

Abstract

Plantazolicin (PZN) is a ribosomally synthesized and post-translationally modified natural product from Bacillus methylotrophicus FZB42 and Bacillus pumilus. Extensive tailoring to twelve of the fourteen amino acid residues in the mature natural product endows PZN with not only a rigid, polyheterocyclic structure, but also antibacterial activity. Here we report a remarkably discriminatory activity of PZN toward Bacillus anthracis, which rivals a previously-described gamma (γ) phage lysis assay in distinguishing B. anthracis from other members of the Bacillus cereus group. We evaluate the underlying cause of this selective activity by measuring the RNA expression profile of PZN-treated B. anthracis, which revealed significant upregulation of genes within the cell envelope stress response. PZN depolarizes the B. anthracis membrane like other cell envelope-acting compounds but uniquely localizes to distinct foci within the envelope. Selection and whole-genome sequencing of PZN-resistant mutants of B. anthracis implicate a relationship between the action of PZN and cardiolipin (CL) within the membrane. Exogenous CL increases the potency of PZN in wild type B. anthracis and promotes the incorporation of fluorescently tagged PZN in the cell envelope. We propose that PZN localizes to and exacerbates structurally compromised regions of the bacterial membrane, which ultimately results in cell lysis.

KEYWORDS:

Bacillus anthracis; Ribosomally synthesized and post-translationally modified natural product; anthrax; antibiotic; membrane depolarization; mode of action; oxazole; pathogen specific antibiotic; thiazole

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