Diversity of fatty acid susceptibility among clinical isolates of Staphylococcus aureus and its role in membrane potential

Staphylococcus aureus colonizes human skin, nasal cavity, and oral mucosa and causes opportunistic infections. Host-derived fatty acids exhibit antibacterial activity against S. aureus , but the diversity and determinants of fatty acid susceptibility among clinical isolates remain unclear. Here, we evaluated seven C14–C18 fatty acids selected from a physiologically relevant range of host-associated lipids. Linoleic acid (LA), palmitoleic acid (POA), and γ-linolenic acid (GLA) demonstrated significant antibacterial activity. We then analyzed LA and POA susceptibility in 253 clinical isolates. LA minimum inhibitory concentrations (MICs) ranged widely from 18.75 to 1,200 μM, whereas POA MICs clustered between 37.5 and 150 μM. Low-LA-susceptibility strains showed higher baseline membrane potential-associated signals and weaker LA-induced depolarization. Anaerobic culture and srrA inactivation reduced both of these signals and LA MICs. These findings indicate that membrane potential contributes to the heterogeneity of LA susceptibility and provide insight into host fatty acid-mediated control of S. aureus.