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

Proceedings of the National Academy of Sciences of the United States of America
Jhih-Hang JiangAnton Y Peleg

Abstract

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 previou...Continue Reading

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Citations

May 6, 2020·Journal of Bacteriology·Zachary DeMarsJeffrey L Bose
Apr 2, 2020·Frontiers in Immunology·Sebastián A RiquelmeAlice Prince
Dec 4, 2020·International Journal of Molecular Sciences·Marcin MakowskiSónia Gonçalves
Mar 3, 2021·Proceedings of the National Academy of Sciences of the United States of America·Yu-Ling ChangUNKNOWN with the MRSA Systems Immunology Group
Dec 30, 2020·Chemical Reviews·Jed F Fisher, Shahriar Mobashery
Aug 24, 2021·Journal of Clinical and Translational Science·Fleur M KeijElke H J Krekels
Oct 12, 2021·FEBS Letters·Cristian Rocha-RoaCamilo Aponte-Santamaría

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