title: Plantazolicin is an ultra-narrow spectrum antibiotic that targets theBacillus anthracismembrane.
abstract: Plantazolicin (PZN) is a ribosomally synthesized and post-translationally modified natural product fromBacillus methylotrophicusFZB42 andBacillus 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 towardBacillus anthracis, which rivals a previously-described gamma (γ) phage lysis assay in distinguishingB. anthracisfrom other members of theBacillus cereusgroup. We evaluate the underlying cause of this selective activity by measuring the RNA expression profile of PZN-treatedB. anthracis, which revealed significant upregulation of genes within the cell envelope stress response. PZN depolarizes theB. anthracismembrane like other cell envelope-acting compounds but uniquely localizes to distinct foci within the envelope. Selection and whole-genome sequencing of PZN-resistant mutants ofB. anthracisimplicate a relationship between the action of PZN and cardiolipin (CL) within the membrane. Exogenous CL increases the potency of PZN in wild typeB. anthracisand 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.
authors.affiliation: 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.
authors.forename: Katie J
authors.initials: KJ
authors.lastname: Molohon
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801.
authors.forename: Patricia M B
authors.initials: PMB
authors.lastname: Saint-Vincent
authors.affiliation: Department of Physics and Center for the Physics of Living Cells, University of Illinois at Urbana-Champaign, Urbana, IL 61801.
authors.forename: Seongjin
authors.initials: S
authors.lastname: Park
authors.affiliation: Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801.
authors.forename: James R
authors.initials: JR
authors.lastname: Doroghazi
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801.
authors.forename: Tucker
authors.initials: T
authors.lastname: Maxson
authors.affiliation: Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD 21702.
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Hershfield
authors.affiliation: Department of Crop Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801.
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Flatt
authors.affiliation: Department of Crop Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801.
authors.forename: Nathan E
authors.initials: NE
authors.lastname: Schroeder
authors.affiliation: 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.
authors.forename: Taekjip
authors.initials: T
authors.lastname: Ha
authors.affiliation: 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.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Mitchell
keywords: Bacillus anthracis; Ribosomally synthesized and post-translationally modified natural product; anthrax; antibiotic; membrane depolarization; mode of action; oxazole; pathogen specific antibiotic; thiazole