Staphylococcus aureusprophages are gatekeepers of lipid utilization to control membrane plasticity, bacterial fitness, and antibiotic adaptation

Abstract

Lipids are essential components of bacterial membranes and phages are quasi-ubiquitous in bacteria. Both are crucial mediators of bacteria-host interactions. In the major pathogen Staphylococcus aureus, two common prophages, f11.1 and f13, are preferentially integrated in lipases genes: respectively encoding Geh, a triglyceride lipase, and Hlb, a sphingomyelinase. Here we discovered that f11.1 and f13 prophage statuses interactively determine bacterial growth, fatty acid (FA) incorporation and elongation via their synthesis pathway (FASII), and membrane composition. Remarkably, FASII-mediated elongation of C18:2 issued from triglycerides was stimulated by intact Geh, i.e., in non-Φ11.1 lysogens. Secondly, while hlb has no direct role in triglyceride metabolism, it inhibited C18:2 incorporation from di- and tri-glycerides into bacterial membrane as observed in non-Φ13 lysogens. We show that these interactions are based on competition between Geh-generated fatty acids from tri- and di-glycerides, and Hlb-generated C16, for binding the fatty acid kinase FakB1 subunit. These findings lead to a mechanistic model in which prophage regulates the dynamics of lipid utilization, which in turn dictates FA toxicity, FASII activity and bacterial fitness. We suggest that testing new therapeutics against S. aureus should consider prophage status and environmental lipids for accurate prediction of efficiency.