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An antibiotic that inhibits a late step in wall teichoic acid biosynthesis induces the cell wall stress stimulon in Staphylococcus aureus.

Authors
  • Campbell, Jennifer
  • Singh, Atul K
  • Swoboda, Jonathan G
  • Gilmore, Michael S
  • Wilkinson, Brian J
  • Walker, Suzanne
Type
Published Article
Journal
Antimicrobial Agents and Chemotherapy
Publisher
American Society for Microbiology
Publication Date
Apr 01, 2012
Volume
56
Issue
4
Pages
1810–1820
Identifiers
DOI: 10.1128/AAC.05938-11
PMID: 22290958
Source
Medline
License
Unknown

Abstract

Wall teichoic acids (WTAs) are phosphate-rich, sugar-based polymers attached to the cell walls of most Gram-positive bacteria. In Staphylococcus aureus, these anionic polymers regulate cell division, protect cells from osmotic stress, mediate host colonization, and mask enzymatically susceptible peptidoglycan bonds. Although WTAs are not required for survival in vitro, blocking the pathway at a late stage of synthesis is lethal. We recently discovered a novel antibiotic, targocil, that inhibits a late acting step in the WTA pathway. Its target is TarG, the transmembrane component of the ABC transporter (TarGH) that exports WTAs to the cell surface. We examined here the effects of targocil on S. aureus using transmission electron microscopy and gene expression profiling. We report that targocil treatment leads to multicellular clusters containing swollen cells displaying evidence of osmotic stress, strongly induces the cell wall stress stimulon, and reduces the expression of key virulence genes, including dltABCD and capsule genes. We conclude that WTA inhibitors that act at a late stage of the biosynthetic pathway may be useful as antibiotics, and we present evidence that they could be particularly useful in combination with beta-lactams.

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