Trimethoprim exerts its antimicrobial effect by inhibiting which enzyme in the bacterial folate synthesis pathway?

Explanation

## Mechanism of Trimethoprim **Key Point:** Trimethoprim inhibits bacterial dihydrofolate reductase (DHFR), the enzyme that converts dihydrofolate to tetrahydrofolate (THF). ### Folate Synthesis Pathway The bacterial folate synthesis pathway has two critical steps: 1. **Dihydropteroate synthase** — catalyzes condensation of PABA with pteridine to form dihydropteroate (inhibited by sulfonamides) 2. **Dihydrofolate reductase** — converts dihydrofolate to tetrahydrofolate, the active cofactor for one-carbon transfer reactions (inhibited by trimethoprim) ### Why Trimethoprim is Selective Bacterial DHFR has a ~1000-fold higher affinity for trimethoprim compared to mammalian DHFR, allowing selective toxicity. This selectivity permits its use as a systemic antimicrobial agent. ### Synergy with Sulfonamides When trimethoprim and sulfonamides are combined (co-trimoxazole), they act sequentially on the folate pathway: - Sulfonamide blocks dihydropteroate synthase (step 1) - Trimethoprim blocks dihydrofolate reductase (step 2) This sequential blockade produces bactericidal synergy and is the basis for the fixed-dose combination. **High-Yield:** The combination is more potent than either agent alone because it blocks two consecutive steps in the same metabolic pathway, preventing compensatory bypass. **Clinical Pearl:** Resistance to trimethoprim typically arises from mutations in DHFR that reduce drug binding affinity, not from enzyme overproduction.