In Staphylococcus aureus , the acyl-CoA synthetase MbcS supports branched-chain fatty acid synthesis from carboxylic acid and aldehyde precursors

In the human pathogen Staphylococcus aureus , branched-chain fatty acids (BCFAs) are the most abundant fatty acids in membrane phospholipids, and strains deficient for their synthesis experience BCFAs auxotrophy in laboratory culture and attenuated virulence during infection. Thus, membrane integrity is essential for S. aureus pathogenesis. Furthermore, the membrane of S. aureus is among the main targets for antibiotic therapy. Therefore, determining the mechanisms involved in BCFAs synthesis is critical to manage S. aureus infections. Here, we report that overexpression of the bona fide acyl-CoA synthetase gene mbcS (formerly SAUSA300_2542) restores BCFAs synthesis in strains lacking the canonical biosynthetic pathway catalyzed by the branched-chain a-keto acid dehydrogenase (BKDH) complex. We demonstrate that the acyl-CoA synthetase activity of MbcS activates branched-chain carboxylic acids, and is required by S. aureus to utilize the isoleucine derivative 2-methylbutyraldehyde to restore BCFAs synthesis in S. aureus . Based on the ability of some staphylococci to convert branched-chain aldehydes into their respective branched-chain carboxylic acids and our findings demonstrating that branched-chain aldehydes are in fact BCFAs precursors, we propose that MbcS promotes the scavenging of exogenous branched-chain carboxylic acids (BCCAs) and mediates branched-chain fatty acids synthesis via a de novo alternative pathway.