Host-dependent resistance of Group A Streptococcus to sulfamethoxazole mediated by a horizontally-acquired ECF transporter S component

Abstract Described antimicrobial resistance mechanisms enable bacteria to avoid the direct effects of antibiotics and can be monitored by in vitro susceptibility testing and genetic methods. We have identified a new mechanism of sulfamethoxazole resistance that requires a host metabolite for activity. Using a combination of in vitro evolution and metabolic rescue experiments, we identified an energy-coupling factor (ECF) transporter S component gene (thfT) that enables Group A Streptococcus to acquire extracellular tetrahydrofolate and related compounds. ThfT likely modifies the substrate specificity of an ECF transporter to acquire the end products of folate biosynthesis. As ThfT-mediated resistance is undetectable by routine surveillance methods, our study highlights the need to understand antibiotic susceptibility during infection to reduce inappropriate antibiotic use and treatment failures.