Antibiotic resistance and host immune evasion in <i>Staphylococcus aureus</i> mediated by a metabolic adaptation

Abstract

<i>Staphylococcus aureus</i> is a notorious human bacterial pathogen with considerable capacity to develop antibiotic resistance. We have observed that human infections caused by highly drug-resistant <i>S. aureus</i> are more prolonged, complicated, and difficult to eradicate. Here we describe a metabolic adaptation strategy used by clinical <i>S. aureus</i> 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, <i>cls2</i>, encoding cardiolipin synthase. Single <i>cls2</i> 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 <i>cls2</i> point mutations also allowed <i>S. aureus</i> 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 <i>S. aureus</i> to circumvent antibiotic and immune attack and provide crucial insights into membrane-based therapeutic targeting of this troublesome pathogen.