What is the mechanism of Trimethoprim?

Trimethoprim is an antibiotic that is primarily used to treat bacterial infections. To understand its mechanism, it is essential to delve into the biochemical processes it disrupts within bacterial cells. Trimethoprim specifically inhibits bacterial dihydrofolate reductase (DHFR), an enzyme critical for the synthesis of tetrahydrofolic acid (THF). THF is a form of folic acid and is essential for the synthesis of nucleotides, which are the building blocks of DNA.

Bacterial cells, unlike human cells, synthesize their own folic acid. This synthesis pathway involves several enzymatic steps, one of which is the reduction of dihydrofolate (DHF) to THF by the enzyme DHFR. Trimethoprim selectively binds to bacterial DHFR with a much higher affinity than it does to the mammalian counterpart. This selective binding effectively blocks the conversion of DHF to THF in bacteria, leading to a depletion of THF. Without THF, bacteria cannot produce the nucleotides required for DNA replication and cell division, thereby inhibiting bacterial growth and proliferation.

Trimethoprim's specificity for bacterial DHFR over human DHFR is a critical aspect of its safety profile, minimizing its impact on human cells while effectively targeting bacterial cells. This selectivity reduces the risk of adverse effects that could arise from the inhibition of human DHFR, which is also involved in nucleotide synthesis but through a different pathway and structural characteristics.

In clinical practice, Trimethoprim is often used in combination with another antibiotic, sulfamethoxazole, in a formulation known as co-trimoxazole. The combination works synergistically by targeting two different enzymes in the folic acid synthesis pathway. While Trimethoprim inhibits DHFR, sulfamethoxazole inhibits an earlier step in the pathway, specifically the enzyme dihydropteroate synthase. This dual blockade results in a more effective disruption of folic acid synthesis, making it harder for bacteria to develop resistance compared to when either drug is used alone.

The use of Trimethoprim, either alone or in combination, is particularly effective against a range of Gram-positive and Gram-negative bacteria. It is commonly prescribed for urinary tract infections, respiratory infections, gastrointestinal infections, and certain types of diarrhea. However, the development of bacterial resistance to Trimethoprim is an ongoing concern. Bacteria can acquire resistance through various mechanisms, such as mutations in the DHFR enzyme that reduce the binding affinity of Trimethoprim, or through the acquisition of plasmids that encode resistant forms of the enzyme.

In summary, the mechanism of Trimethoprim involves the inhibition of bacterial dihydrofolate reductase, leading to a disruption in folic acid synthesis and subsequently hindering bacterial DNA production and cell division. Its selective action against bacterial DHFR, combined with its use in combination therapies, underscores its significance in treating various bacterial infections while highlighting the challenges posed by antibiotic resistance.