TY - JOUR
T1 - Mutual potentiation drives synergy between trimethoprim and sulfamethoxazole
AU - Minato, Yusuke
AU - Dawadi, Surendra
AU - Kordus, Shannon L.
AU - Sivanandam, Abiram
AU - Aldrich, Courtney C.
AU - Baughn, Anthony D.
N1 - Funding Information:
We thank Peter Southern for critical reading of the manuscript and helpful comments, Bruce Witthuhn for expert technical assistance with LC-MS/MS analysis, Arkady B. Khodursky for providing us the E. coli single-gene deletion mutants, Ryan C. Hunter for providing S. aureus USA300, and Betsy Hirsch for providing E. coli B11. We also thank Allison Bauman for her excellent technical assistance. This work was supported by a grant from the University of Minnesota Academic Health Center Faculty Research Development Program to A.D.B. and C.C.A., and by startup funds from the University of Minnesota to A.D.B. and C.C.A.
Publisher Copyright:
© The Author(s) 2018.
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-018-03447
DO - 10.1038/s41467-018-03447
M3 - Article
C2 - 29520101
AN - SCOPUS:85047955974
VL - 9
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 1003
ER -