The double-edged role of FASII regulator FabT in Streptococcus pyogenes infection

In Streptococcus pyogenes, the fatty acid (FA) synthesis pathway FASII is feedback-controlled by the FabT repressor bound to an acyl-Acyl carrier protein. Despite FabT defects being linked to reduced virulence in animal models, spontaneous fabT mutants arise in vivo. To resolve this paradox, we characterized the conditions and mechanisms that require FabT activity, and those that promote fabT mutant emergence. The primary fabT mutant defect is energy dissipation: specific nutrients are consumed, but the mutant fails to grow on human tissue, cells, or cell filtrates where nutrients are limited. These features explain the FabT requirement during infection. Conversely, fabT mutants exhibited a marked growth advantage over the wild-type in biotopes rich in saturated FAs. fabT mutants emerge in this context, where continued FASII activity prevented environmental FA incorporation. An ex vivo muscle model demonstrated that wild-type S. pyogenes was inhibited, while fabT mutant growth was stimulated, but conditional to FASII activity. Our findings elucidate the rationale for emerging fabT mutants that improve survival in lipid-rich biotopes, but lead to a genetic impasse for infection. ### Competing Interest Statement The authors have declared no competing interest.