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