Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, VIC 3800, Australia.
Department of Materials Science and Engineering, Faculty of Engineering, Monash University, Clayton, VIC 3800, Australia.
Proc Natl Acad Sci U S A. 2019 Feb 26;116(9):3722-3727. doi: 10.1073/pnas.1812066116. Epub 2019 Feb 11.
is a notorious human bacterial pathogen with considerable capacity to develop antibiotic resistance. We have observed that human infections caused by highly drug-resistant are more prolonged, complicated, and difficult to eradicate. Here we describe a metabolic adaptation strategy used by clinical 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, , encoding cardiolipin synthase. Single 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 point mutations also allowed 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 to circumvent antibiotic and immune attack and provide crucial insights into membrane-based therapeutic targeting of this troublesome pathogen.
是一种臭名昭著的人类细菌病原体，具有相当大的能力产生抗生素耐药性。我们已经观察到，由高度耐药的引起的人类感染更加持久、复杂且难以根除。在这里，我们描述了临床分离株使用的一种代谢适应策略，该策略导致对最后一线抗生素达托霉素的耐药性，同时还影响宿主先天免疫。这种反应的特征是，磷脂生物合成基因编码的心脏脂合酶发生点突变，导致阴离子膜磷脂成分发生变化。单个点突变足以引起达托霉素耐药性、抗生素治疗失败和持续感染。这些表型是通过增强心脏脂合成介导的，导致细菌膜心磷脂增加和磷脂酰甘油减少。膜磷脂谱的变化导致膜结构的改变，从而阻碍了达托霉素的渗透和膜的破坏。点突变还使能够逃避中性粒细胞趋化作用，这是由细菌膜磷脂酰甘油减少介导的，这是以前未描述的细菌驱动趋化作用。总之，这些数据说明了 逃避抗生素和免疫攻击的代谢策略，并为针对这种麻烦病原体的基于膜的治疗靶点提供了重要的见解。
