@article{616e807a31ce421e87c609ea72492100,
title = "Plantazolicin Is an Ultranarrow-Spectrum Antibiotic That Targets the Bacillus anthracis Membrane",
abstract = "Plantazolicin (PZN) is a ribosomally synthesized and post-translationally modified natural product from Bacillus methylotrophicus FZB42 and Bacillus pumilus. Extensive tailoring to 12 of the 14 amino acid residues in the mature natural product endows PZN with not only a rigid, polyheterocyclic structure, but also antibacterial activity. Here we report the 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 up-regulation 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, anthrax, antibiotic, membrane depolarization, mode of action, oxazole, pathogen specific antibiotic, ribosomally synthesized and post-translationally modified natural product, thiazole",
author = "Molohon, {Katie J.} and Blair, {Patricia M.} and Seongjin Park and Doroghazi, {James R.} and Tucker Maxson and Hershfield, {Jeremy R.} and Flatt, {Kristen M.} and Schroeder, {Nathan E.} and Taekjip Ha and Mitchell, {Douglas A.}",
note = "Funding Information: This work was supported by the U.S. National Institutes of Health (1R01 GM097142 to DAM) and the Defense Threat Reduction Agency under USAMRIID (Project 922141). K.J.M., P.M.B., and J.R.D. were supported in part by a James R. Beck Graduate Research Fellowship, an ACS Medicinal Chemistry Predoctoral Fellowship, and the Carle R. Woese Institute for Genomic Biology Fellows program, respectively. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the U.S. Army. We are grateful to the Pasteur Institute, BEI Resources, O. Schneewind (University of Chicago), C. Turnbough (University of Alabama Birmingham), U.S. Department of Agriculture, The Caenorhabditis Genetics Center, The Bacillus Genetic Stock Center, S. Shozhamannan (The Naval Medical Research Center), V. Fischetti (Rockefeller University), C. Marston (Center for Disease Control and Prevention), D. de Mendoza (Universidad Nacional de Rosario), J. Wells (University of California - San Francisco), J. Helmann (Cornell University), M. So (University of Arizona), P. Hergenrother (University of Illinois at Urbana-Champaign), H. Zhao University of Illinois at Urbana-Champaign), P. Hanna (Univeristy of Michigan), and S. Leppla (National Institute of Allergy and Infectious Diseases) for providing strains and plasmids used in this study; Dr. Yao Shao Qin and Dr. Li Zhengqiu (National University of Singapore) for providing 2-(2-azidoethyl)-2-(but-3-ynyl)-1,3-dioxolane; as well as Teresa Abshire, Stephanie Halasohoris, and Lynda Miller (U.S. Army Medical Research Institute for Infectious Diseases, USAMRIID) for providing us with γ phage and their assistance. We also thank C. Deane for critical review of the manuscript. Publisher Copyright: {\textcopyright} 2015 American Chemical Society.",
year = "2016",
month = mar,
day = "11",
doi = "10.1021/acsinfecdis.5b00115",
language = "English (US)",
volume = "2",
pages = "207--220",
journal = "ACS Infectious Diseases",
issn = "2373-8227",
publisher = "American Chemical Society",
number = "3",
}