An Antibiotic That Inhibits a Late Step in Wall Teichoic Acid Biosynthesis Induces the Cell Wall Stress Stimulon in Staphylococcus aureus
An Antibiotic That Inhibits a Late Step in Wall Teichoic Acid Biosynthesis Induces the Cell Wall Stress Stimulon in Staphylococcus aureus
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DOI：
10.1128/aac.05938-11
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发表时间：
2012-04-01
影响因子：
4.9
通讯作者：
Walker, Suzanne
中科院分区：
文献类型：
--
作者：
Campbell, Jennifer;Singh, Atul K.;Walker, Suzanne
壁磷壁酸 (WTA) 是富含磷酸盐的糖基聚合物，附着在大多数革兰氏阳性细菌的细胞壁上。在金黄色葡萄球菌中，这些阴离子聚合物调节细胞分裂，保护细胞免受渗透压，介导宿主定植，并掩盖酶敏感的肽聚糖键。尽管 WTA 不是体外存活所必需的，但在合成后期阻断该途径是致命的。我们最近发现了一种新型抗生素 targocil，它可以抑制 WTA 途径中的后期作用步骤。其目标是 TarG，ABC 转运蛋白 (TarGH) 的跨膜成分，可将 WTA 输出到细胞表面。我们使用透射电子显微镜和基因表达谱检查了 targocil 对金黄色葡萄球菌的影响。我们报告说，targocil 处理导致含有肿胀细胞的多细胞簇，显示出渗透应激的证据，强烈诱导细胞壁应激刺激，并减少关键毒力基因的表达，包括 dlt-ABCD 和荚膜基因。我们得出的结论是，在生物合成途径后期起作用的 WTA 抑制剂可能可用作抗生素，并且我们提供的证据表明它们与 β-内酰胺联合使用特别有用。
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 dlt-ABCD 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.