What is the mechanism of Tetroxoprim?

Tetroxoprim is a synthetic antibacterial agent that belongs to the class of diaminopyrimidines. It exhibits broad-spectrum bacteriostatic activity, making it effective against a wide range of Gram-positive and Gram-negative bacteria. Understanding the mechanism of action of Tetroxoprim requires delving into its biochemical interactions and the specific pathways it targets within bacterial cells.

At the molecular level, Tetroxoprim functions by inhibiting bacterial dihydrofolate reductase (DHFR). DHFR is a crucial enzyme in the folate synthesis pathway, which is vital for the production of tetrahydrofolic acid, a form of folate that is necessary for the synthesis of nucleic acids and proteins. By binding to DHFR, Tetroxoprim prevents the reduction of dihydrofolate to tetrahydrofolate, thereby blocking the production of thymidine, purines, and ultimately DNA and RNA.

The inhibition of DHFR by Tetroxoprim is competitive, meaning that the drug competes with the natural substrate, dihydrofolic acid, for binding to the active site of the enzyme. This competitive inhibition is highly effective because Tetroxoprim has a higher affinity for bacterial DHFR compared to human DHFR, allowing for selective toxicity towards bacterial cells while minimizing the impact on human cells.

Additionally, Tetroxoprim is often used in combination with sulfonamides, such as sulfamethoxazole, to create a synergistic antibacterial effect. Sulfonamides inhibit the enzyme dihydropteroate synthase, which is an earlier step in the folate synthesis pathway. By jointly targeting two sequential steps in the same metabolic pathway, the combination of Tetroxoprim and a sulfonamide greatly enhances antibacterial efficacy and reduces the likelihood of resistance development.

Resistance to Tetroxoprim can occur through various mechanisms. One common method is through the acquisition of plasmid-mediated genes that encode for a resistant form of DHFR with reduced affinity for the drug. Mutations in the chromosomal gene encoding DHFR can also lead to resistance. Additionally, bacteria may increase the production of DHFR, thus overcoming the inhibition by Tetroxoprim.

In summary, Tetroxoprim exerts its antibacterial effects by inhibiting the bacterial enzyme dihydrofolate reductase, thereby disrupting the folate synthesis pathway and ultimately hindering DNA and RNA production. Its selective action on bacterial cells and potential for synergistic use with sulfonamides make it a valuable agent in the treatment of various bacterial infections. However, the emergence of resistance remains a significant challenge, underscoring the need for cautious and judicious use of this antibiotic.