Abstract
Trimethoprim (TMP)-sulfamethoxazole (SMX) is a synergistic antimicrobial drug combination used to treat various bacterial and certain fungal infections. It was previously understood that this drug combination is synergistic because these two drugs inhibit sequential steps of the bacterial folate biosynthesis pathway. SMX inhibits the production of the tetrahydrofolate (THF) precursor dihydropteroate, and TMP inhibits the conversion of dihydrofolate (DHF) to THF. Consequently, SMX potentiates TMP by limiting de novo DHF production, and this mono-potentiation mechanism was the previous explanation for their synergistic action. We demonstrated that this model is insufficient to explain the potent synergy of TMP-SMX. Using genetic and biochemical approaches, we characterize a metabolic feedback loop in which THF is critical for producing the folate precursor dihydropterin pyrophosphate (DHPPP). We reveal that TMP potentiates SMX activity through the inhibition of DHPPP synthesis. Our study demonstrates that the mutual potentiation of the action of each drug on the other drives the TMP-SMX synergy. These findings highlight the importance of metabolic pathway structure in understanding antimicrobial drug interactions. In this talk, I will introduce our strategy to identify additional pathways that can be explored for potently synergistic drug targets.
