Trimethoprim bacterial DHFR inhibition

Stone and Morrison (25) reported that both methotrexate and trimethoprim were good Inhibitors of E. coll DHFR (Kl 3.6 and 0.49 nM, respectively), while trimethoprim was much less potent on the chicken DHFR than methotrexate (Kl=3,530 and 1.3 nM, respectively). As expected from the sequence similarities between GSH and DHFRs In Figure 2 that Indicated that GSH Is similar to avian rather than bacterial DHFRs, trimethoprim was a less potent Inhibitor of GSH than methotrexate by about five-fold. Thus the Inhibition spectrum of GSH by the two DHFR Inhibitors corresponded well to the degree of sequence similarities of GSH to avian and bacterial DHFRs. 

The action of trimethoprim (43) as an antibacterial depends on its inhibition of the bacterial enzyme dihydrofolate reductase (DHFR). The essential coenzyme tetrahydrofolate (47) operates in a cyclic process where the nucleotide thymidylate (48) is synthesized whilst... 

A classic example of a drug that works by species-specific protein inhibition is trimethoprim (TMP). Because this drug binds to bacterial dihydrofolate reductase (DHFR) 10 moie tightly than to the mammalian enzyme, there is a therapeutic concentration in which the drug can be used as an antibacterial with little deleterious consequences for a mammalian host. 

Trimethoprim should not be used in combination with pyrimethamine since both drugs are DHFR inhibitors, although pyrimethamine is more selective for the protozoal enzyme and trimethoprim for the bacterial enzyme. When used together, trimethoprim competitively inhibits pyrimethamine, thus decreasing the efficacy of this more effective compound. In addition, pyrimethamine and trimethoprim have at least... 

A most interesting and useful development concerning DHR inhibitors was the selectivity of inhibition observed between different classes of compounds against dihydrofolate reductases from mammals, protozoa and bacteria, which was found to be due to marked differences in binding affinity to the enzyme methotrexate binds very tightly to all reductases tested and is lethal to any cell it can enter, while trimethoprim and pyrimethamine have selectively strong affinity for bacterial and plasmodial reductases, respectively. This helped to rationalise the clinical use of DHFR inhibitors alone or in combination with sulphonamides and sulphones while trimethoprim is used mainly for bacterial infections, pyrimethamine is used for protozoal infections [58a]. 

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