Antibiotic resistance and host immune evasion in Staphylococcus aureus mediated by a metabolic adaptation
Antibiotic resistance and host immune evasion in Staphylococcus aureus mediated by a metabolic adaptation
复制标题
DOI：
10.1073/pnas.1812066116
复制
发表时间：
2019-02-26
影响因子：
11.1
通讯作者：
Peleg, Anton Y.
中科院分区：
文献类型：
--
作者：
Jiang, Jhih-Hang;Bhuiyan, Md Saruar;Peleg, Anton Y.
金黄色葡萄球菌是一种臭名昭著的人类细菌病原体，具有相当大的发展抗生素耐药性的能力。我们已经观察到由高度耐药的S。金黄色葡萄球菌感染的时间更长，更复杂，更难根除。在这里，我们描述了临床S。金黄色葡萄球菌菌株，导致对最后一种抗生素达托霉素的耐药性，同时影响宿主的先天免疫。这种反应的特点是由磷脂生物合成基因，cls2，编码心磷脂合酶的点突变诱导的阴离子膜磷脂组成的变化。单个cls2点突变足以导致达托霉素耐药、抗生素治疗失败和持续感染。这些表型介导的增强心磷脂的生物合成，导致增加细菌膜心磷脂和减少磷脂酰甘油。膜磷脂谱的变化导致膜结构的改变，损害达托霉素渗透和膜破坏。cls2点突变也允许S.金黄色葡萄球菌逃避中性粒细胞趋化性，介导的减少细菌膜磷脂酰甘油，以前未描述的细菌驱动的化学引诱物。总之，这些数据说明了S.金黄色葡萄球菌规避抗生素和免疫攻击，并提供关键的见解，基于膜的治疗靶向这种麻烦的病原体。
Staphylococcus aureus is a notorious human bacterial pathogen with considerable capacity to develop antibiotic resistance. We have observed that human infections caused by highly drug-resistant S. aureus are more prolonged, complicated, and difficult to eradicate. Here we describe a metabolic adaptation strategy used by clinical S. aureus strains that leads to resistance to the last-line antibiotic, daptomycin, and simultaneously affects host innate immunity. This response was characterized by a change in anionic membrane phospholipid composition induced by point mutations in the phospholipid biosynthesis gene, cls2, encoding cardiolipin synthase. Single cls2 point mutations were sufficient for daptomycin resistance, antibiotic treatment failure, and persistent infection. These phenotypes were mediated by enhanced cardiolipin biosynthesis, leading to increased bacterial membrane cardiolipin and reduced phosphatidylglycerol. The changes in membrane phospholipid profile led to modifications in membrane structure that impaired daptomycin penetration and membrane disruption. The cls2 point mutations also allowed S. aureus to evade neutrophil chemotaxis, mediated by the reduction in bacterial membrane phosphatidylglycerol, a previously undescribed bacterial-driven chemoattractant. Together, these data illustrate a metabolic strategy used by S. aureus to circumvent antibiotic and immune attack and provide crucial insights intomembranebased therapeutic targeting of this troublesome pathogen.