title: An antibiotic that inhibits a late step in wall teichoic acid biosynthesis induces the cell wall stress stimulon in Staphylococcus aureus.
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.
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Campbell
authors.forename: Atul K
authors.initials: AK
authors.lastname: Singh
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Swoboda
authors.forename: Michael S
authors.initials: MS
authors.lastname: Gilmore
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Wilkinson
authors.forename: Suzanne
authors.initials: S
authors.lastname: Walker
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001329:Autolysis; D001426:Bacterial Proteins / Q000378:metabolism; D002473:Cell Wall / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D003470:Culture Media; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D046228:Microarray Analysis; D008826:Microbial Sensitivity Tests; D008854:Microscopy, Electron; D046529:Microscopy, Electron, Transmission; D011799:Quinazolines / Q000494:pharmacology*; D012329:RNA, Bacterial / Q000235:genetics / Q000302:isolation & purification; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D013682:Teichoic Acids / Q000096:biosynthesis*; D014158:Transcription, Genetic / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology*; D037521:Virulence Factors / Q000096:biosynthesis / Q000235:genetics; D047090:beta-Lactams / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D003470:Culture Media; D011799:Quinazolines; D012329:RNA, Bacterial; D013682:Teichoic Acids; D014230:Triazoles; D037521:Virulence Factors; D047090:beta-Lactams; C560795:targocil