Long chain fatty acids are found on human mucous membranes, skin and in abscesses and some are proposed to form an important antimicrobial component of the innate immune system. Despite this, little is known about their antibacterial mechanism and how bacteria respond to them.

To investigate their mode of action transcriptomic and proteomic analyses of Staphylococcus aureus MRSA252 treated with fatty acids were performed using microarrays, qRT-PCR and 2D-SDS-PAGE. Altered expression of the stress-response genes of the CtsR and SigmaB regulons was observed. Further key pathways showing changed levels of gene expression included the peptidoglycan biosynthesis pathway, the glycolysis and gluconeogenesis pathway and pigment production. These results were confirmed by qRT-PCR. In addition several virulence-associated genes displayed altered levels of expression in response to fatty acids. Most notably the quorum sensing agr locus showed increased expression under all of the fatty acid treatment conditions used in this study, whilst the opposite effect on agr expression was observed in the S. aureus SH1000 strain, corroborating previously published data. S. aureus fatty acid survival mutants were isolated by inactivation of target loci identified from microarrays or by screening transposon libraries. Moreover, the importance of specific loci in virulence was determined in a murine arthritis model.

The accumulated data contests previous claims for single targets for these physiologically important antimicrobial agents and suggests a more complex antibacterial action.