Synthetic lethal compound combinations reveal a fundamental connection between wall teichoic acid and peptidoglycan biosyntheses in Staphylococcus aureus.
Synthetic lethal compound combinations reveal a fundamental connection between wall teichoic acid and peptidoglycan biosyntheses in Staphylococcus aureus.
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DOI：
10.1021/cb100269f
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发表时间：
2011-01-21
影响因子：
4
通讯作者：
Walker, Suzanne
中科院分区：
文献类型：
--
作者：
Campbell, Jennifer;Singh, Atul K.;Maria, John P. Santa, Jr.;Kim, Younghoon;Brown, Stephanie;Swoboda, Jonathan G.;Mylonakis, Eleftherios;Wilkinson, Brian J.;Walker, Suzanne
金黄色葡萄球菌的甲氧西林耐药性取决于mecA的产生，mecA编码青霉素结合蛋白2A（PBP 2A），这是一种获得性肽聚糖转肽酶（TP），对β-内酰胺类抗生素的敏感性降低。当天然TP被β-内酰胺抑制时，PBP 2A交联新生肽聚糖。尽管mecA表达对于β-内酰胺耐药性至关重要，但这还不够。在这里，我们表明，通过抑制途径中的第一种酶TarO来阻断壁磷壁酸（WTA）的表达，使MRSA菌株对β-内酰胺类药物敏感，即使β-内酰胺耐药转肽酶PBP 2A仍然表达。TarO抑制剂和β-内酰胺类药物之间的显著协同作用值得注意，这不仅仅是因为克服耐甲氧西林沙门氏菌的策略。金黄色葡萄球菌（MRSA）的TPs活性是迫切需要的，但因为在MRSA菌株中，TarO和天然TPs的活性都不是必需的。抑制TarO和天然TP的“合成致死性”表明在S.金黄色。事实上，透射电子显微镜显示S。在WTA合成中被阻断的金黄色葡萄球菌细胞在分隔和细胞分离方面具有广泛的缺陷，表明细胞壁组装和降解失调。我们的研究表明，WTA在S.金黄色葡萄球菌细胞分裂，并提高了合成的致死化合物组合可能具有克服抗生素抗性细菌感染的治疗效用的可能性。
Methicillin resistance in Staphylococcus aureus depends on the production of mecA, which encodes penicillin-binding protein 2A (PBP2A), an acquired peptidoglycan transpeptidase (TP) with reduced susceptibility to beta-lactam antibiotics. PBP2A crosslinks nascent peptidoglycan when the native TPs are inhibited by beta-lactams. Although mecA expression is essential for beta-lactam resistance, it is not sufficient. Here we show that blocking the expression of wall teichoic acids (WTAs) by inhibiting the first enzyme in the pathway, TarO, sensitizes MRSA strains to beta-lactams even though the beta-lactam-resistant transpeptidase, PBP2A, is still expressed. The dramatic synergy between TarO inhibitors and beta-lactams is noteworthy not simply because strategies to overcome methicillin-resistant S. aureus (MRSA) are desperately needed, but because neither TarO nor the activities of the native TPs are essential in MRSA strains. The “synthetic lethality” of inhibiting TarO and the native TPs suggests a functional connection between ongoing WTA expression and peptidoglycan assembly in S. aureus. Indeed, transmission electron microscopy shows that S. aureus cells blocked in WTA synthesis have extensive defects in septation and cell separation, indicating dysregulated cell wall assembly and degradation. Our studies imply that WTAs play a fundamental role in S. aureus cell division and raise the possibility that synthetic lethal compound combinations may have therapeutic utility for overcoming antibiotic resistant bacterial infections.
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影响因子：
3.2
作者：
McAleese, F;Wu, SW;Tomasz, A
通讯作者：
Tomasz, A
影响因子：
3.2
作者：
BECK, WD;BERGERBACHI, B;KAYSER, FH
通讯作者：
KAYSER, FH
影响因子：
--
作者：
Huber, Joann;Donald, Robert G. K.;Roemer, Terry
通讯作者：
Roemer, Terry
影响因子：
3.2
作者：
Gründling, A;Schneewind, O
通讯作者：
Schneewind, O
影响因子：
3.6
作者：
Pinho, MG;Errington, J
通讯作者：
Errington, J