Trimethoprim antibacterial activity

Trimethoprim (a weak base) concentrates in prostatic fluid and in vaginal fluid, which are more acidic than plasma. Therefore, it has more antibacterial activity in prostatic and vaginal fluids than many other antimicrobial drugs. 

Polymyxin B is bactericidal fc>r most gram-negative organisms, especially Haemophilus and Pseudomonas species. Neisseria and Proteus species, however, are resistant. Combining polymyxin B with bacitracin or trimethoprim achieves broad-spectrum antibacterial activity for treating acute bacterial conjunctivitis. Because it is not absorbed through mucous membrane or skin tissue, polymyxin B is used primarily for superficial infections.Adverse reactions are rare. 

The antihistaminic phenothiazine trimeprazine has significant antibacterial activity in vitro and in vivo, and a combination with trimethoprim is highly synergistic, as shown in vivo in Swiss white mice using Salmonella typhimurium as the challenge bacterium (200). 

Brogden RN, Carmine AA, Heel RC, Speight TM, Avery GS. Trimethoprim a review of its antibacterial activity, pharmacokinetics and therapeutic use in urinary tract infections. Drugs 1982 23(6) 405-30. 

USAN] Gantanol ) is a sulphonamide with antibacterial activity, used in the treatment of respiratory and urinary tract infections. It is usually used in conjunction with trimethoprim (co-trimoxazole). sulphamethoxydiazine [ban] (suifametoxydiazine... 

In order to counteract resistance development and to improve antibacterial activity, sulfonamides are typically combined with an inhibitor of dihydrofolate reductase (Figure 2, i). Dihydrofolate reductase is a core enzyme of human central intermediary metabolism. Although the bacterial and mammalian dihydrofolate reductases are orthologues with considerable sequence similarity, trimethoprim (35) has sufficient selectivity to enable the selective inhibition of the parasite enzyme. 

Increased activity of enzymes that make drags more polar is likely to inactivate an antimicrobial drug and will not lead to increased antibacterial activity. Specific examples of mechanisms that do result in synergy include (A) the combination of trimethoprim and sulfamethoxazole (B) the combination of a penicillin and an aminoglycoside and (D) the combination of clavu-lanic acid and amoxicillin. The answer is (C). 

For the highest antibacterial activity in vertebrates, the 2,4-diamino-pyrimidines require that the massive lipophilic substituent be modified with a slightly hydrophilic outer area. The best of these compounds proved to be trimethoprim 4,8) (Roth, Falco, and Hitchings, 1962). It can be seen from Table 4.2 that pyrimethamine is most selective against the malarial parasite enzyme, whereas trimethoprim is selective against a bacterial... 

The methylation of deoxyuridine monophosphate (dUMP) to thymidine monophosphate (TMP), catalyzed by thymidylate synthase, is essential for the synthesis of DNA. The one-carbon fragment of methy-lene-tetrahydrofolate is reduced to a methyl group with release of dihydrofolate, which is then reduced back to tetrahydrofolate by dihydrofolate reductase. Thymidylate synthase and dihydrofolate reductase are especially active in tissues with a high rate of cell division. Methotrexate, an analog of 10-methyl-tetrahydrofolate, inhibits dihydrofolate reductase and has been exploited as an anticancer drug. The dihydrofolate reductases of some bacteria and parasites differ from the human enzyme inhibitors of these enzymes can be used as antibacterial drugs, eg, trimethoprim, and anti-malarial drugs, eg, pyrimethamine. 

Rapidly dividing cells need an abundant supply of dTMP for DNA synthesis, and this creates a need for dihydrofolate reductase activity. Specific dihydrofolate reductase inhibitors have become especially useful as antibacterials, e.g. trimethoprim, and antimalarial drugs, e.g. pyrimethamine. 

Zhou W, Moore DE. Photosensitizing activity of the antibacterial drugs sulfamethoxazole and trimethoprim. Photochem Photobiol 1997 39 63-72. 

Folate analogs such as trimethoprim have potent antibacterial and antiprotozoal activity. Trimethoprim binds lO -fold less tightly to mammalian dihydrofolate reductase than it does to reductases of susceptible microorganisms. Small differences in the active-site clefts of these enzymes account for its highly selective antimicrobial action. The combination of trimethoprim and sulfamethoxazole (an inhibitor of folate synthesis) is widely used to treat infections. 

Trimethoprim is a diaminopyrimidine structure which has proved to be a highly selective, orally active, antibacterial, and antimalarial agent. Unlike the sulfonamides, it acts against dihydrofolate reductase—the enzyme which carries out the conversion of folic acid to tetrahydrofolate. The overall effect, however, is the same as with sulfonamides—the inhibition of DNA synthesis and cell growth. 

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