Lipase-mediated detoxification of host-derived antimicrobial fatty acids byStaphylococcus aureus

Abstract

AbstractLong-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 asStaphylococcus aureus. These antimicrobial fatty acids (AFAs) elicit bacterial adaptation strategies, which have yet to be fully elucidated. Characterizing the pervasive mechanisms used byS. aureusto resist AFAs could open new avenues to prevent pathogen colonization. Here, we identify theS. aureuslipase Lip2 as a novel resistance factor against AFAs. Lip2 detoxifies AFAs via esterification with cholesterol. This is reminiscent of the activity of the fatty acid-modifying enzyme (FAME), whose identity has remained elusive for over three decades.In vitro, Lip2-dependent AFA-detoxification was apparent during planktonic growth and biofilm formation. Our genomic analysis 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 ofS. aureusskin colonization, bacteria were protected from sapienic acid - a human-specific AFA - in a cholesterol- and lipase-dependent manner. These results suggest Lip2 is the long-sought FAME that exquisitely manipulates environmental lipids to promote bacterial growth. Our data support a model in whichS. aureusexploits and/or exacerbates lipid disorders to colonize otherwise inhospitable niches.