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    Antibiotic resistance and host immune evasion in Staphylococcus aureus mediated by a metabolic adaptation

    Year: 2019

    Journal: Proc. Natl. Acad. Sci. U. S. A., Volume 116, 1-Feb, page 3722–3727

    Authors: Jiang, Jhih-Hang; Bhuiyan, Md Saruar; Shen, Hsin-Hui; Cameron, David R.; Rupasinghe, Thusitha W. T.; Wu, Chun-Ming; Le Brun, Anton P.; Kostoulias, Xenia; Domene, Carmen; Fulcher, Alex J.; McConville, Malcolm J.; Howden, Benjamin P.; Lieschke, Graham J.; Peleg, Anton Y.

    Organizations: CASS Foundation [SM/12/4276]; NHMRC Practitioner FellowshipNational Health and Medical Research Council of Australia; Australian National Health and Medical Research Council (NHMRC)National Health and Medical Research Council of Australia [APP1144303]; NHMRC Career Development FellowshipNational Health and Medical Research Council of Australia; Australian Research CouncilAustralian Research Council [LE150100110]; State Government of Victoria; Australian GovernmentAustralian Government

    Keywords: S. aureus; daptomycin; cardiolipin; phosphatidylglycerol; neutrophils

    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.
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