Extracellular detoxification of host-derived antimicrobial fatty acids by Staphylococcus aureus

Long-chain fatty acids with antimicrobial properties are abundant on the skin and mucosal surfaces, where they are essential to restrict the proliferation of opportunistic pathogens such as Staphylococcus aureus. These antimicrobial fatty acids (AFAs) elicit bacterial adaptation strategies, which have yet to be fully elucidated. Characterizing mechanisms used by S. aureus to resist AFAs could open new avenues to prevent pathogen colonization, which is the overarching goal of our research program. For instance, we have used mutagenesis, recombinant proteins, click-chemistry, high-performance thin layer chromatography and ultra-high performance liquid chromatography-electrospray ionization-tandem mass spectrometry to unveil S. aureus lipase Lip2 as a resistance factor against AFAs. Lip2 detoxifies AFAs via esterification with cholesterol. Lip2-dependent AFA-detoxification was apparent during planktonic growth and biofilm formation. Importantly, Lip2 is also secreted into the extracellular milieu as a major component of S. aureus membrane vesicles (MVs). In a previous study, we have demonstrated that these hydrophobic MVs act as decoys to bind AFAs and protect bacteria from AFA toxicity. Our newfound role of Lip2 strongly suggests that MVs could serve as platform to sequester AFAs, which are then converted in situ into innocuous fatty acid esters by Lip2. Indeed, Lipase-proficient MVs complement a lipase-deficient mutant and enable the bacterium to grow in the presence of otherwise toxic AFA concentrations. Besides, our genomic analysis of over three thousand genomes of S. aureus revealed that prophage-mediated inactivation of Lip2 was more common in blood and nose isolates than in skin strains, suggesting a particularly important role of Lip2 for skin colonization. Accordingly, in a mouse model of S. aureus skin colonization, bacteria were protected from sapienic acid (a human-specific AFA) in a cholesterol- and lipase-dependent manner. Taken together, our results suggest that S. aureus exoproducts target and transform environmental lipids in unforeseen ways with possible implications for the bacterium"s ability to colonize and infect its host.