Staphylococcal lipases generate wax esters to detoxify host-derived antimicrobial fatty acids.

Host-derived antimicrobial fatty acids (AFAs) are essential to restrict the proliferation of opportunistic microorganisms like Staphylococcus aureus. This bacterium has evolved several adaptation strategies to resist AFAs. Recently, we have discovered that S. aureus utilizes its lipase Lip2 to esterify AFAs with cholesterol, leading to AFA detoxification. However, the full extent of staphylococcal lipase-mediated changes of the host lipid landscape remains elusive. For instance, fatty acids esterified with long-chain fatty alcohols (wax esters), that play important roles for skin structure and function, could represent products or substrates of staphylococcal lipases. Wax ester production from AFAs and long-chain fatty alcohols as a strategy to escape the AFA toxicity is unexplored. Here, we demonstrate that Lip2 detoxifies AFAs with various fatty alcohols via esterification. This enabled Lip2-expressing S. aureus to grow and form biofilms in the presence of fatty alcohols and otherwise toxic concentrations of AFAs. Moreover, we investigated lipases from coagulase-negative staphylococci (CoNS), which share similarities with Lip2, for esterification capacities. To do so, we heterologously expressed CoNS lipases in a lipase-deficient S. aureus mutant. The Staphylococcus simulans SsL and Staphylococcus epidermidis GehD lipases could protect the S. aureus lipase-deficient mutant from AFA toxicity in the presence of either cholesterol or fatty alcohols. Our current lipidomics analyses are revealing the ability of Lip2 and CoNS lipases in shaping the lipid landscape of the bacterium and its environment. Collectively, these results suggest that (i) lipase-mediated AFA detoxification is common in CoNS, (ii) different hydroxylated substrates found on the skin surface can be used to alleviate the toxicity of AFAs and (iii) lipases exquisitely manipulate environmental lipids to promote bacterial growth while changing the host lipid landscape. Considering their ability to both degrade lipids and detoxify AFAs, staphylococcal lipases may play an underappreciated role at the host-microbe interface with potential implications for the microbiome composition.