Ftsh Sensitizes Methicillin-Resistant Staphylococcus aureus to β-Lactam Antibiotics by Degrading YpfP, a Lipoteichoic Acid Synthesis Enzyme.
Ftsh Sensitizes Methicillin-Resistant Staphylococcus aureus to β-Lactam Antibiotics by Degrading YpfP, a Lipoteichoic Acid Synthesis Enzyme.
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DOI：
10.3390/antibiotics10101198
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发表时间：
2021-10-01
期刊：
影响因子：
--
通讯作者：
Bae T
中科院分区：
文献类型：
--
作者：
Yeo WS;Jeong B;Ullah N;Shah MA;Ali A;Kim KK;Bae T
在革兰氏阳性病原菌金黄色葡萄球菌中，FtsH是一种膜结合金属蛋白酶，在细菌的毒力和抗逆性中起着关键作用。这种蛋白酶也已知使耐甲氧西林金黄色葡萄球菌（MRSA）对β-内酰胺抗生素敏感;然而，分子机制尚不清楚。在这里，通过对FtsH底物突变体的分析，我们发现FtsH通过降解合成脂磷壁酸（LTA）的锚分子的酶YpfP而使MRSA特异性地对β-内酰胺类敏感。FtsH的过度表达和ypfP致敏的MRSA对β-内酰胺类抗生素的破坏均被观察到。ftsH和ypfP的敲除突变增加了细胞壁的厚度。β-内酰胺致敏与异常大的LTA分子的产生相一致。rpoC、vraB和SAUSA300_2133基因中的三种突变的组合阻断了FtsH的β-内酰胺致敏作用。鼠感染ypfP突变体可以用苯唑西林治疗，苯唑西林是一种对MRSA无效的β-内酰胺抗生素;然而，苯唑西林的有效浓度取决于S。金黄色葡萄球菌我们的研究表明，FtsH的β-内酰胺增敏作用是由于其消化YpfP。这也表明较大的LTA分子是β-内酰胺致敏表型的原因，YpfP是开发新型抗MRSA药物的可行靶标。
In the Gram-positive pathogen Staphylococcus aureus, FtsH, a membrane-bound metalloprotease, plays a critical role in bacterial virulence and stress resistance. This protease is also known to sensitize methicillin-resistant Staphylococcus aureus (MRSA) to β-lactam antibiotics; however, the molecular mechanism is not known. Here, by the analysis of FtsH substrate mutants, we found that FtsH sensitizes MRSA specifically to β-lactams by degrading YpfP, the enzyme synthesizing the anchor molecule for lipoteichoic acid (LTA). Both the overexpression of FtsH and the disruption of ypfP-sensitized MRSA to β-lactams were observed. The knockout mutation in ftsH and ypfP increased the thickness of the cell wall. The β-lactam sensitization coincided with the production of aberrantly large LTA molecules. The combination of three mutations in the rpoC, vraB, and SAUSA300_2133 genes blocked the β-lactam-sensitizing effect of FtsH. Murine infection with the ypfP mutant could be treated by oxacillin, a β-lactam antibiotic ineffective against MRSA; however, the effective concentration of oxacillin differed depending on the S. aureus strain. Our study demonstrated that the β-lactam sensitizing effect of FtsH is due to its digestion of YpfP. It also suggests that the larger LTA molecules are responsible for the β-lactam sensitization phenotype, and YpfP is a viable target for developing novel anti-MRSA drugs.
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影响因子：
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