An Antibiotic That Inhibits a Late Step in Wall Teichoic Acid Biosynthesis Induces the Cell Wall Stress Stimulon in Staphylococcus aureus

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>Wall teichoic acids (WTAs) are phosphate-rich, sugar-based polymers attached to the cell walls of most Gram-positive bacteria. In<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">Staphylococcus aureus</jats:named-content>, 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<jats:italic>in vitro</jats:italic>, 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<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">S. aureus</jats:named-content>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<jats:italic>dltABCD</jats:italic>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.</jats:p>

Primary Mode of Action of &lt;i&gt;Cistus ladaniferus&lt;/i&gt; L. Essential Oil Active Fractions on &lt;i&gt;Staphylococcus aureus&lt;/i&gt; Strain

“…These observations suggest a blocking in cell division. Campbell et al [18] reported similar effects for S. aureus cells treated with targocil, an antibiotic that induces cell wall stress by inhibiting a late step in wall teichoic acid synthesis. Blocking of this biosynthetic pathway is lethal for bacterial cells and this could explain the rapid bactericidal effect induced by alcohol fraction in 1 h of treatment.…”

DNA Targeting as a Likely Mechanism Underlying the Antibacterial Activity of Synthetic Bis-Indole Antibiotics

“…To determine whether these compounds act directly on the cell wall synthetic pathway, we measured the effect of the bis-indoles and netropsin on a strain of S. aureus carrying a reporter construct that produces a bioluminescent signal in response to inhibitors of cell wall synthesis. The reporter construct consists of the promoter of vraX, which is induced by inhibitors of cell wall and teichoic acid synthesis and is part of the cell wall stress stimulon [CWSS] (15,16,38), that has been fused to a bacterial luciferase operon (luxABCDE) carried on plasmid (pAmi-vraX). As shown in Fig.…”

Dissecting the regulation of bile-induced biofilm formation in Staphylococcus aureus

“…In line with this, the inhibition of WTA synthesis by deletion of LytR-CpsA-Psr proteins has been shown to increase the basal expression of the 'cell wall stress stimulon', a collection of genes responsible for mounting a general cell wall stress-response in the presence of cell wall damaging-agents (Dengler et al, 2012). The recently discovered antibiotic targocil, which blocks expression of tagG, has also been shown to induce cell wall stress in S. aureus (Campbell et al, 2012). It is plausible that in the hyper-biofilm mutants identified in the present study, the transposon insertions reduce WTA biosynthesis, thereby stimulating a more profound cell wall stress-response in the presence of bile.…”