This study shows that S. aureus is more versatile than recently concluded. First, mutants selected on the FabI inhibitor triclosan are about 100-fold more frequent when fatty acids are available. A novel FASII bypass target is identified as FabD, a malonyl CoA-acyl carrier protein transacylase.

Antimicrobials targeting the fatty acid synthesis pathway (FASII) may be bypassed by numerous pathogens that incorporate host fatty acids. This activity would greatly restrict use of anti-FASII drugs. However, the status of Staphylococcus aureus is controversial, based on suggestions that major self-synthesized branched chain fatty acids are essential. This study shows that S. aureus is more versatile than recently concluded. First, mutants selected on the FabI inhibitor triclosan are about 100-fold more frequent when fatty acids are available. A novel FASII bypass target is identified as FabD, a malonyl CoA-acyl carrier protein transacylase. A fabDG196R point substitution grows normally in standard conditions, is triclosan resistant in the presence of fatty acids, and is fully infectious in mice. A fabD knock-out mutant is a triclosan-resistant FA auxotroph, which persists in mice over six days, the time of most antibiotic treatments. The fabD mutants are refractive to both FabI and FabF inhibitors, consistent with FASII bypass. Moreover, they show greater resistance to two unrelated antibiotics. We predicted and showed that staphylococci carrying fabD polymorphisms already exist in commensal and hospital S. aureus populations and bypass FASII, indicating that such variants are competitive in nature. We hypothesize that fatty-acid-rich infection reservoirs such as skin and nares are selection sites for emergence of FASII bypass variants when confronted with FASII inhibitors.