Bacterial dihydrofolate

Transcarbamoylase Aldose reductase Bacterial dihydrofolate reductase Phosphodiesterase... 

Figure 1.4 Left panel Space filing model of the structure of bacterial dihydrofolate reductase with methotrexate bound to the active site. Right panel Close-up view of the active site, illustrating the structural complementarity between the ligand (methotrexate) and the binding pocket. See color insert. Source Courtesy of Nesya Nevins.

Figure 1.4 Top panel Space filing model of the structure of bacterial dihydrofolate reductase with...

Trimethoprim is a pyrimidine derivative (diaminopyrimidine) related to antimalarial drug pyrimethamine, which selectively inhibits bacterial dihydrofolate reductase, necessary for the conversion of dihydrofolate to tetrahydrofolic acid. Sulfonamides act by inhibiting the incorporation of PABA into dihydrofolate by bacteria. A combination of... 

Trimethoprim, a trimethoxybenzylpyrimidine, selectively inhibits bacterial dihydrofolic acid reductase, which converts dihydrofolic acid to tetrahydrofolic acid, a step leading to the synthesis of purines and ultimately to DNA (Figure 46-2). Trimethoprim is about 50,000 times less efficient in inhibition of mammalian dihydrofolic acid reductase. Pyrimethamine, another benzylpyrimidine, selectively inhibits dihydrofolic acid reductase of protozoa compared with that of mammalian cells. As noted above, trimethoprim or pyrimethamine in combination with a sulfonamide blocks sequential steps in folate synthesis, resulting in marked enhancement (synergism) of the activity of both drugs. The combination often is bactericidal, compared with the bacteriostatic activity of a sulfonamide alone. 

Trimethoprim [trye METH oh prim], a potent inhibitor of bacterial dihydrofolate reductase3, exhibits an antibacterial spectrum similar to the sulfonamides. However, trimethoprim is most often compounded with sulfamethoxazole. 

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. 

C. D. Selassie, Z. Fang, R. Li, C. Hansch, G. Debnath, T. E. Klein, R. Langridge, and B. T. Kaufman. On the structure selectivity problem in drug design. A comperative study of benzylpyrimidine inhibition of vertebrate and bacterial dihydrofolate reductase via molecular graphics and quantitative structure-activity relationships. Journal of Medicinal Chemistry, 32 1895-1905, 1989. 

The observant reader may have noticed that this is similar to the mode of action of trimethoprim [Chapter 9, page 157]. Trimethoprim is selective for bacterial cells because bacterial dihydrofolate reductase is many times more sensitive to trimethoprim than is the human enzyme.)... 

Trimethoprim [2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine, 43, (Figure 25.4) is a potent and selective inhibitor of bacterial dihydrofolate. It is used alone or in combination with sulfamethoxazole to treat a wide range of clinical bacterial infections. 

Trimethoprim is used as an antibiotic because it binds to bacterial dihydrofolate reductase much more tightly than to mammalian dihydrofolate reductase. 

Trimethoprim Trimethoprim is a selective inhibitor of bacterial dihydrofolate reductase that prevents formation of the active tetrahydro form of folic acid (Figure 46-1). Bacterial dihydrofolate reductase is four to five orders of magnitude more sensitive to inhibition by trimethoprim than the mammalian enzyme. 

Due to a mutation in the human genome, trimetoprim inhibits bacterial dihydrofolate reductase but not mammalian dihydrofolate reductase. Trimetoprim has therefore been used in combination with the sulphonamides to provide synergism in activity while reducing the toxidty potential of the individual compounds. A usefiil dinical example is co-trimoxazole, which is a compound formulation of trimetoprim and sulfamethoxazole. 

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