Mutations in mmpL and in the cell wall stress stimulon contribute to resistance to oxadiazole antibiotics in methicillin-resistant Staphylococcus aureus.
Mutations in mmpL and in the cell wall stress stimulon contribute to resistance to oxadiazole antibiotics in methicillin-resistant Staphylococcus aureus.
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mmpL 和细胞壁应激刺激的突变导致耐甲氧西林金黄色葡萄球菌对恶二唑类抗生素产生耐药性。
DOI：
10.1128/aac.03501-14
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发表时间：
2014
影响因子：
4.9
通讯作者：
Mobashery,Shahriar
中科院分区：
文献类型：
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作者：
Xiao,Qiaobin;Vakulenko,Sergei;Chang,Mayland;Mobashery,Shahriar
金黄色葡萄球菌是医院和社区获得性感染的主要原因，对各种抗生素表现出广泛的耐药性。我们最近发现了恶二唑类抗生素，它对耐甲氧西林金黄色葡萄球菌(MRSA)具有体外和体内活性。我们在此报告了MMPL，一个可能的耐药、结瘤和细胞分裂(RND)家族的成员，在金黄色葡萄球菌Col株中与恶二唑耐药有关。通过连续传代，我们产生了两个金黄色葡萄球菌Col变种，显示出对恶二唑抗生素的敏感性降低。恶二唑对一个菌株(指定为金黄色葡萄球菌)的最低抑菌浓度(MIC)可重复增加2倍(至4μg/ml)，而对另一个菌株(金黄色葡萄球菌)，其最低抑菌浓度(MIC)增加4倍(至8μg/ml，溶解度极限)。COLR株系由COLI株衍生而来。全基因组测序发现金黄色葡萄球菌COLR有31个突变，其中29个与大肠杆菌相同。与我们之前发现的恶二唑抗生素抑制细胞壁生物合成一致，我们发现了13个突变，这些突变要么发生在细胞壁应激刺激基因的结构基因中，要么发生在基因的启动子中。金黄色葡萄球菌COLR中两个独特的突变是编码硫氧还蛋白(SACOL1794)和MMPL(SACOL2566)的两个基因的替换。通过基因缺失和互补实验，确定了mpLin对恶二唑的抗性作用。据我们所知，这是第一次报道细胞壁作用的抗生素选择细胞壁应力Stimulon的突变，也是第一次发现MMPL与金黄色葡萄球菌对抗生素的耐药性有关。
Staphylococcus aureus is a leading cause of hospital- and community-acquired infections, which exhibit broad resistance to various antibiotics. We recently disclosed the discovery of the oxadiazole class of antibiotics, which hasin vitroandin vivoactivities against methicillin-resistant S. aureus (MRSA). We report herein that MmpL, a putative member of the resistance, nodulation, and cell division (RND) family of proteins, contributes to oxadiazole resistance in the S. aureus strain COL. Through serial passages, we generated two S. aureus COL variants that showed diminished susceptibilities to an oxadiazole antibiotic. The MICs for the oxadiazole against one strain (designated S. aureus COLI) increased reproducibly 2-fold (to 4 μg/ml), while against the other strain (S. aureus COLR), they increased >4-fold (to >8 μg/ml, the limit of solubility). The COLRstrain was derived from the COLIstrain. Whole-genome sequencing revealed 31 mutations in S. aureus COLR, of which 29 were shared with COLI. Consistent with our previous finding that oxadiazole antibiotics inhibit cell wall biosynthesis, we found 13 mutations that occurred either in structural genes or in promoters of the genes of the cell wall stress stimulon. Two unique mutations in S. aureus COLRwere substitutions in two genes that encode the putative thioredoxin (SACOL1794) and MmpL (SACOL2566). A role formmpLin resistance to oxadiazoles was discerned from gene deletion and complementation experiments. To our knowledge, this is the first report that a cell wall-acting antibiotic selects for mutations in the cell wall stress stimulon and the first to implicate MmpL in resistance to antibiotics in S. aureus.