Fletcher et al., 2025

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 agr 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 these SCFAs on <i>S. aureus</i> fitness and their ubiquity as metabolites in the human host also suggests that they may be effective as adjuvants to traditional antimicrobial agents when used in combination.