Commensal-derived short-chain fatty acids disrupt lipid membrane homeostasis in <i>Staphylococcus aureus</i>

The role of commensal anaerobic bacteria in chronic respiratory infections is unclear, yet they can exist in abundances comparable to canonical pathogens <i>in vivo</i>. Their contributions to the metabolic landscape of the host environment may influence pathogen behavior by competing for nutrients and creating inhospitable conditions via toxic metabolites. Here, we show that the anaerobe-derived short-chain fatty acids (SCFAs) propionate and butyrate negatively affect <i>Staphylococcus aureus</i> physiology by disrupting branched-chain fatty acid (BCFA) metabolism. In turn, alterations to BCFA abundance impair <i>S. aureus</i> growth, compromise membrane integrity, diminish expression of the accessory gene regulator quorum-sensing system, and increase sensitivity to membrane-targeting antimicrobials. Disrupted BCFA metabolism also reduced <i>S. aureus</i> fitness in competition with <i>Pseudomonas aeruginosa</i>, suggesting that airway microbiome composition and the metabolites they exchange can directly impact pathogen succession over time. The pleiotropic effects of SCFAs on <i>S. aureus</i> fitness and their ubiquity as metabolites in the human host also suggest that they may be effective as adjuvants to traditional antimicrobial agents when used in combination.IMPORTANCE<i>Staphylococcus aureus</i> is a primary pathogen of chronic airway disease yet is also found in the upper airways of 30%-50% of the population to no obvious detriment. Thus, identifying the host and/or microbial factors that tip the balance between its commensal and pathogenic states may be key to its control. Here, we reveal that short-chain fatty acids produced by commensal microbiota promote a marked remodeling of the <i>S. aureus</i> lipid membrane that, in turn, sensitizes the pathogen to antimicrobials, disrupts accessory gene regulator quorum signaling, and reduces its competitive fitness. Altogether, these data suggest that co-colonizing microbiota and the metabolites they exchange with <i>S. aureus</i> may be key players in the microbial ecology of airway disease.