Trimethoprim Triprim

Structural Formula nh2

Ball-and-Stick Model nh2

0CH3

0CH3

Year of discovery: 1956 (G.H. Hitchings); Year of introduction: 1973 (in combination with sulfamethoxazole as Bactrim or Cotrimoxazole or Septra); 1980 (as the single drug Triprim); Drug category: Diaminopyrimidine/dihydrofolate reductase inhibitor (antifolate); Main uses: For the treatment of urinary tract infections, travelers' diarrhea, respiratory and middle ear infections; Other brand names: Proloprim, Monotrim.

Tetrahydrofolate, a metabolite of folic acid, is essential for normal cell division in both humans and bacteria. Humans require dietary folic acid because they cannot produce it. Most bacteria, however, make their own folic acid from a pteridine derivative (orange) and para-aminobenzoic acid (blue). This process is catalyzed by the enzyme dihydropteroate synthase (DHPS). The two-step conversion of folic acid to tetrahydrofolate is catalyzed by dihydrofolate reductase (DHFR). It was recognized in the 1940s that the inhibition of either one (or both) of these enzymes would block bacterial growth and reproduction.

Pteridine derivative

Dihydropteroate Synthase (DHPS)

Pteridine derivative

Tetrahydrofolate I

Sulfonamides

Trimethoprim rCH

N NH

Dihydropteroic acid r

Tetrahydrofolate I

Glutamate

DHFR + NADPH

Sulfanilamide and several of its derivatives are wide-spectrum antibiotics, effective against both Gram-positive and Gramnegative bacteria. They bind to the enzyme DHPS, as mimics of para-aminobenzoic acid, and inhibit folic acid biosynthesis. Unfortunately, sulfonamide-resistant strains emerged fairly soon after the introduction of "sulfa" drugs. For this reason sulfonamides now are rarely used alone. Resistance develops because a minute fraction of bacteria can use the low levels of folate provided by the host and these bacteria proliferate.

H2N'

Sulfanilamide

Sulfamethoxazole

-ch3

However, the combination of diamino-pyrimidines such as trimethoprim and sulfonamides is very effective in antibacterial therapy.1 Trimethoprim is a selective inhibitor of the bacterial enzyme DHFR (cf. methotrexate, page 46) and prevents the production of tetrahydrofolate from folic acid. It was found that the 20:1 combination of sulfamethoxazole and trimethoprim is synergistic and provides optimal antibiotic therapy.

Trimethoprim binds selectively to bacterial DHFR enzyme rather than the human enzyme because of subtle differences in the tetrahydrofolate binding site.2 The X-ray structure of trimethoprim bound to the bacterial enzyme DHFR has been determined.3 The picture below shows NADPH (silver) and trimethoprim (red) bound to DHFR (yellow).

1. Arch. Intern Med. 2003, 163, 402-410; 2. Curr. Med. Chem. 2006, 13. 377-398; 3. J. Mol. Biol. 2000, 295, 307323 (1DG5); Refs. p. 175
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