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Inhibition of Precursor Synthesis: Trimethoprim

المؤلف:  Peter Chin-Hong, Elizabeth A. Joyce, Manjiree Karandikar, Mehrdad Matloubian, Luis Alberto Rubio, Brian S. Schwartz, Warren Levinson

المصدر:  Levinsons Review of Medical Microbiology & Immunology: A Guide to Clinical Infectious Diseases (2024)

الجزء والصفحة:  18th E , P74

2026-09-07

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Trimethoprim inhibits the production of tetrahydrofolic acid by a different mechanism from that of the sulfonamides, namely it inhibits the enzyme dihydrofolate reductase (see Figure 1). Its specificity for bacteria is based on its much greater affinity for bacterial reductase than for the human enzyme.

Mechanism of action of sulfonamides and trimethoprim. A: Comparison of the structures of p-aminobenzoic acid (PABA) and sulfanilamide. Note that the only difference is that PABA has a carboxyl (COOH) group, whereas sulfanilamide has sulfonamide (SO2NH2) group. B: Structure of trimethoprim. C: Inhibition of the folic acid pathway by sulfonamide and trimethoprim. Sulfonamides inhibit the synthesis of dihydrofolic acid (DHF) from its precursor PABA. Trimethoprim inhibits the synthesis of tetrahydrofolic acid (THF) from its precursor DHF. Loss of THF inhibits DNA synthesis because THF is required to transfer a methyl group onto uracil to produce thymidine, an essential component of DNA.

Trimethoprim is used most frequently together with sulfamethoxazole. Note that both drugs act on the same pathway but at different sites to inhibit the synthesis of tetrahydrofolate. The advantages of the combination are that (1) bacterial mutants resistant to one drug will be inhibited by the other and (2) the two drugs can act synergistically (i.e., when used together, they cause significantly greater inhibition than the sum of the inhibition caused by each drug separately).

Trimethoprim-sulfamethoxazole is clinically useful in the treatment of UTIs, Pneumocystis pneumonia, and shigellosis. It is also used for prophylaxis in neutropenic patients to prevent opportunistic infections.