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Mutual potentiation drives synergy between trimethoprim and sulfamethoxazole

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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)

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.

Suggested Citation

  • Yusuke Minato & Surendra Dawadi & Shannon L. Kordus & Abiram Sivanandam & Courtney C. Aldrich & Anthony D. Baughn, 2018. "Mutual potentiation drives synergy between trimethoprim and sulfamethoxazole," Nature Communications, Nature, vol. 9(1), pages 1-7, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03447-x
    DOI: 10.1038/s41467-018-03447-x
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    Cited by:

    1. M. Kalindu D. Rodrigo & Aarti Saiganesh & Andrew J. Hayes & Alisha M. Wilson & Jack Anstey & Janessa L. Pickering & Jua Iwasaki & Jessica Hillas & Scott Winslow & Tabitha Woodman & Philipp Nitschke & , 2022. "Host-dependent resistance of Group A Streptococcus to sulfamethoxazole mediated by a horizontally-acquired reduced folate transporter," Nature Communications, Nature, vol. 13(1), pages 1-11, December.

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