Plantazolicin Is an Ultranarrow-Spectrum Antibiotic That Targets the Bacillus anthracis Membrane

Katie J. Molohon, Patricia M. Blair, Seongjin Park, James R. Doroghazi, Tucker Maxson, Jeremy R. Hershfield, Kristen M. Flatt, Nathan E. Schroeder, Taekjip Ha, Douglas A. Mitchell

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)207-220
Number of pages14
JournalACS Infectious Diseases
Volume2
Issue number3
DOIs
StatePublished - Mar 11 2016
Externally publishedYes

Fingerprint

Bacillus anthracis
Anti-Bacterial Agents
Cardiolipins
Membranes
Biological Products
Bacillus cereus
Bacteriophages
Bacillus
Up-Regulation
Genome
RNA
Amino Acids
Genes
plantazolicin B

Keywords

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

ASJC Scopus subject areas

  • Infectious Diseases

Cite this

Molohon, K. J., Blair, P. M., Park, S., Doroghazi, J. R., Maxson, T., Hershfield, J. R., ... Mitchell, D. A. (2016). Plantazolicin Is an Ultranarrow-Spectrum Antibiotic That Targets the Bacillus anthracis Membrane. ACS Infectious Diseases, 2(3), 207-220. https://doi.org/10.1021/acsinfecdis.5b00115

Plantazolicin Is an Ultranarrow-Spectrum Antibiotic That Targets the Bacillus anthracis Membrane. / Molohon, Katie J.; Blair, Patricia M.; Park, Seongjin; Doroghazi, James R.; Maxson, Tucker; Hershfield, Jeremy R.; Flatt, Kristen M.; Schroeder, Nathan E.; Ha, Taekjip; Mitchell, Douglas A.

In: ACS Infectious Diseases, Vol. 2, No. 3, 11.03.2016, p. 207-220.

Research output: Contribution to journalArticle

Molohon, KJ, Blair, PM, Park, S, Doroghazi, JR, Maxson, T, Hershfield, JR, Flatt, KM, Schroeder, NE, Ha, T & Mitchell, DA 2016, 'Plantazolicin Is an Ultranarrow-Spectrum Antibiotic That Targets the Bacillus anthracis Membrane', ACS Infectious Diseases, vol. 2, no. 3, pp. 207-220. https://doi.org/10.1021/acsinfecdis.5b00115
Molohon, Katie J. ; Blair, Patricia M. ; Park, Seongjin ; Doroghazi, James R. ; Maxson, Tucker ; Hershfield, Jeremy R. ; Flatt, Kristen M. ; Schroeder, Nathan E. ; Ha, Taekjip ; Mitchell, Douglas A. / Plantazolicin Is an Ultranarrow-Spectrum Antibiotic That Targets the Bacillus anthracis Membrane. In: ACS Infectious Diseases. 2016 ; Vol. 2, No. 3. pp. 207-220.
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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.",
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AU - Maxson, Tucker

AU - Hershfield, Jeremy R.

AU - Flatt, Kristen M.

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