{'fraction_non_alphanumeric': 0.01553556827473426, 'fraction_numerical': 0.0012264922322158627, 'mean_word_length': 6.1759530791788855, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Antibiotic resistance and host immune evasion in Staphylococcus aureus mediated by a metabolic adaptation

Significance Staphylococcus aureus is one of the most significant human bacterial pathogens that has the capacity to cause serious infections and become highly resistant to antibiotics. In this study, we identified a metabolic adaptation mechanism used by S. aureus to simultaneously circumvent killing by one of the last-line antistaphylococcal antibiotics, daptomycin, and attack from host innate immune cells. This process led to enhanced bacterial survival and was mediated by a change in bacterial membrane phospholipid composition sufficient to impair daptomycin membrane penetration and significantly affect neutrophil chemotactic responses. These results highlight the importance of bacterial membrane lipid adaptation in bacterial pathogenesis and provide crucial insights into potentially novel therapeutic targeting. 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 into membrane-based therapeutic targeting of this troublesome pathogen.