Mutual potentiation drives synergy between trimethoprim and sulfamethoxazole

Yusuke Minato (), Surendra Dawadi, Shannon L. Kordus, Abiram Sivanandam, Courtney C. Aldrich and Anthony D. Baughn ()
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Yusuke Minato: University of Minnesota Medical School
Surendra Dawadi: University of Minnesota
Shannon L. Kordus: University of Minnesota Medical School
Abiram Sivanandam: University of Minnesota Medical School
Courtney C. Aldrich: University of Minnesota
Anthony D. Baughn: University of Minnesota Medical School

Nature Communications, 2018, vol. 9, issue 1, 1-7

Abstract: Abstract Trimethoprim (TMP)-sulfamethoxazole (SMX) is a widely used synergistic antimicrobial combination to treat a variety of bacterial and certain fungal infections. These drugs act by targeting sequential steps in the biosynthetic pathway for tetrahydrofolate (THF), where SMX inhibits production of the THF precursor dihydropteroate, and TMP inhibits conversion of dihydrofolate (DHF) to THF. Consequently, SMX potentiates TMP by limiting de novo DHF production and this mono-potentiation mechanism is the current explanation for their synergistic action. Here, we demonstrate 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 production of the folate precursor dihydropterin pyrophosphate (DHPPP). We reveal that TMP potentiates SMX activity through inhibition of DHPPP synthesis. Our study demonstrates that the TMP-SMX synergy is driven by mutual potentiation of the action of each drug on the other.

Date: 2018
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DOI: 10.1038/s41467-018-03447-x

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