Inhibition of WTA synthesis blocks the cooperative action of PBPs and sensitizes MRSA to β-lactams.
Inhibition of WTA synthesis blocks the cooperative action of PBPs and sensitizes MRSA to β-lactams.
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DOI：
10.1021/cb300413m
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发表时间：
2013-01-18
影响因子：
4
通讯作者：
Brown, Eric D.
中科院分区：
文献类型：
--
作者：
Farha, Maya A.;Leung, Alexander;Sewell, Edward W.;D'Elia, Michael A.;Allison, Sarah E.;Ejim, Linda;Pereira, Pedro M.;Pinho, Mariana G.;Wright, Gerard D.;Brown, Eric D.
耐药性的增加限制了耐甲氧西林金黄色葡萄球菌（MRSA）感染的治疗选择。在此，我们提供了新的证据，壁磷壁酸（WTA）的生物合成是一个显着的抗菌靶标，具有破坏青霉素结合蛋白（PBP）的协同作用的能力，而PBP是MRSA中β-内酰胺耐药性的基础。编码WTA合成第一步的基因tarO的缺失导致MRSA对β-内酰胺抗生素独特谱的敏感性恢复，该β-内酰胺抗生素对青霉素结合蛋白2（PBP 2）具有已知的选择性。其中，头孢呋辛被用作探针，以筛选先前批准的具有增强其抗MRSA活性的隐蔽能力的药物。噻氯匹定，抗血小板药物Ticlid，强烈增强头孢呋辛，这种协同作用在缺乏tarO的菌株中被废除。该组合在大蜡螟感染模型中也有效。使用遗传和生物化学策略，我们确定噻氯匹定的分子靶点为基因tarO中编码的N-乙酰葡糖胺-1-磷酸转移酶，并提供证据表明WTA生物合成代表了支持PBP 2和PBP 4在S.金黄色。这种方法代表了解决MRSA感染的新范式。
Rising drug resistance is limiting treatment options for infections by methicillin-resistant Staphylococcus aureus (MRSA). Herein we provide new evidence that wall teichoic acid (WTA) biogenesis is a remarkable antibacterial target with the capacity to destabilize the cooperative action of penicillin-binding proteins (PBPs) that underlie β-lactam resistance in MRSA. Deletion of gene tarO, encoding the first step of WTA synthesis, resulted in the restoration of sensitivity of MRSA to a unique profile of β-lactam antibiotics with a known selectivity for penicillin binding protein 2 (PBP2). Of these, cefuroxime was used as a probe to screen for previously approved drugs with a cryptic capacity to potentiate its activity against MRSA. Ticlopidine, the antiplatelet drug Ticlid, strongly potentiated cefuroxime, and this synergy was abolished in strains lacking tarO. The combination was also effective in a Galleria mellonella model of infection. Using both genetic and biochemical strategies, we determined the molecular target of ticlopidine as the N-acetylglucosamine-1-phosphate transferase encoded in gene tarO and provide evidence that WTA biogenesis represents an Achilles heel supporting the cooperative function of PBP2 and PBP4 in creating highly cross-linked muropeptides in the peptidoglycan of S. aureus. This approach represents a new paradigm to tackle MRSA infection.
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影响因子：
8
作者：
Berger-Bächi, B
通讯作者：
Berger-Bächi, B
DOI：
10.1099/00221287-6-1-2-95
发表时间：
1952-01-01
期刊：
JOURNAL OF GENERAL MICROBIOLOGY
影响因子：
--
作者：
DUTHIE, ES;LORENZ, LL
通讯作者：
LORENZ, LL
影响因子：
3.2
作者：
D'Elia, Michael A.;Henderson, James A.;Brown, Eric D.
通讯作者：
Brown, Eric D.
影响因子：
3.2
作者：
D'Elia, Michael A.;Millar, Kathryn E.;Brown, Eric D.
通讯作者：
Brown, Eric D.
影响因子：
--
作者：
D'Elia, Michael A.;Millar, Kathryn E.;Brown, Eric D.
通讯作者：
Brown, Eric D.