Methicillin resistance in Staphylococcus aureus requires glycosylated wall teichoic acids
Methicillin resistance in Staphylococcus aureus requires glycosylated wall teichoic acids
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DOI：
10.1073/pnas.1209126109
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发表时间：
2012-11-13
影响因子：
11.1
通讯作者：
Walker, Suzanne
中科院分区：
文献类型：
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作者：
Brown, Stephanie;Xia, Guoqing;Walker, Suzanne
金黄色葡萄球菌肽聚糖（PG）被称为壁磷壁酸（WTAs）的阴离子聚合物密集功能化。这些聚合物包含三种剪裁修饰：d -丙烯酰化，α - o - glcn酰化和β - o - glcn酰化。在这里，我们描述了一种独特的糖基转移酶TarS的发现和生化表征，该酶将β - o - glcnac （β - o - n -乙酰- d -氨基葡萄糖）残基附着在金黄色葡萄球菌的WTAs上。我们报道耐甲氧西林金黄色葡萄球菌（MRSA）在tarS缺失后对β -内酰胺敏感。与完全缺乏WTAs的菌株不同，WTAs也对β -内酰胺敏感，Delta tarS菌株没有生长或细胞分裂缺陷。由于α - o - glcnac和β - o -葡萄糖修饰都不能产生抗性，因此抗性表型需要对WTA主链β - o - glcnac残基进行高度特异性的化学修饰。这些数据表明- o - glcn酰化的WTAs支架因子是MRSA耐药所必需的。这里鉴定的β - o - glcnac转移酶，即TarS，是使MRSA对β -内酰胺敏感的抗菌剂的独特靶标。
Staphylococcus aureus peptidoglycan (PG) is densely functionalized with anionic polymers called wall teichoic acids (WTAs). These polymers contain three tailoring modifications: D-alanylation, alpha-O-GlcNAcylation, and beta-O-GlcNAcylation. Here we describe the discovery and biochemical characterization of a unique glycosyltransferase, TarS, that attaches beta-O-GlcNAc (beta-O-N-acetyl-D-glucosamine) residues to S. aureus WTAs. We report that methicillin resistant S. aureus (MRSA) is sensitized to beta-lactams upon tarS deletion. Unlike strains completely lacking WTAs, which are also sensitive to beta-lactams, Delta tarS strains have no growth or cell division defects. Because neither alpha-O-GlcNAc nor beta-O-Glucose modifications can confer resistance, the resistance phenotype requires a highly specific chemical modification of the WTA backbone, beta-O-GlcNAc residues. These data suggest beta-O-GlcNAcylated WTAs scaffold factors required for MRSA resistance. The beta-O-GlcNAc transferase identified here, TarS, is a unique target for antimicrobials that sensitize MRSA to beta-lactams.