FabF-FadM Cooperate to Recycle Fatty Acids and Rescue ΔplsX Lethality in Staphylococcus aureus

Phospholipids are essential components of most cell membranes. In Staphylococcus aureus, PlsX acyltransferase is considered indispensable for initiating phospholipid synthesis, unless exogenous fatty acids (FAs) are available for a bypass route. We report that S. aureus can capture internal FAs sources that overcome PlsX essentiality via gain-of-function mutations in two alleles: ΔplsX suppression by a FabF mutation, as mimicked by a FabF antibiotic inhibitor, suggests that FabF stalling causes FA release. Suppressor mutations in FadM, a bifunctional acyl-CoA thioesterase and ACP-binding protein, appear to retain only ACP-binding activity. The fabF and fadM suppressors compensate PlsX forward, but not reverse activity. Remarkably, fabF suppressors emerge only if fadM is present, indicative of FabF-FadM cooperation. We propose that increased ACP binding in FadM suppressor mutants facilitates FA release from FabF-acyl-ACP intermediates. A FabF-FadM relay leading to FA release may contribute to homeostasis between FASII and phospholipid synthesis pathways.