The double-edged role of FASII regulator FabT inStreptococcus pyogenesinfection

Abstract

AbstractInStreptococcus pyogenes, the fatty acid (FA) synthesis pathway FASII is feedback-controlled by the FabT repressor bound to an acyl-Acyl carrier protein. FabT defects are associated with attenuated virulence in animal models. Nevertheless,fabTpoint mutations arisein vivo. To resolve this paradox, we identified conditions and biotopes in whichfabTbehavior is defective, as being human tissues, cells, or cell filtrates. We then defined biotopes in whichfabTmutants have a growth advantage, as being lipid rich. In a proof of concept we demonstrate thatfabTmutants emerge in this context, due to FASII derepression, which prevents environmental FA incorporation. Energy dissipation is identified as the principal defect offabTmutants, such that specific nutrients are consumed but do not promote growth. Our findings elucidate the nature of the link between FabT and virulence, provide a rationale forfabTmutant emergence, and identify the defect that causes attenuatedfabTinfection.