Extracellular wax ester biosynthesis by staphylococcal lipases detoxifies skin fatty acids and shapes interspecies competition.

To maintain its barrier function, human skin requires lipids, including cholesterol, ceramides, free fatty acids, and wax esters. In contrast to other skin lipids, wax esters remain largely unexplored as metabolites of the skin microbiome. Recently, we discovered that Staphylococcus aureus utilises its lipase Lip2 to detoxify antimicrobial fatty acids (AFAs) by esterification with cholesterol. The observed promiscuity of Lip2 and the presence of similar lipases among skin staphylococci prompted the search for novel substrates and products. Here, we identify S. aureus Lip2 and Lip1, Staphylococcus simulans SsL, and Staphylococcus epidermidis GehD and GehC as lipases capable of metabolizing wax esters. These lipases degraded wax esters into AFAs and fatty alcohols, and, except for GehC, shared the ability to esterify AFAs with fatty alcohols, thereby generating wax esters. In monocultures of bacteria heterologously expressing staphylococcal lipases, synthesis of wax esters mirrored protection from AFAs by fatty alcohols in planktonic or biofilm settings. In pairwise cocultures, lipases secreted by lipase-proficient S. aureus, S. simulans, and S. epidermidis functioned as public goods, rescuing lipase-deficient mutants. In the absence of detoxifying substrates/lipases, S. simulans or S. epidermidis outcompeted S. aureus when exposed to AFAs. A skin-mimicking high-salt environment increased the resistance of S. aureus, but not S. simulans, to AFAs, enabling S. aureus to match or outcompete S. simulans in the presence of AFAs or AFAs plus fatty alcohols, respectively. Collectively, our findings suggest that commensal modulation of skin lipids determines whether niche-specific communities are resilient or permissive to pathogenic invasion by S. aureus.