Bacterial dihydropteroate synthase and dihydrofolate reductase (DHPS/DHFR)

Bacterial dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR) are essential enzymes in the microbial folate biosynthetic pathway, which is vital for the production of DNA, RNA, and proteins (StatPearls, 2023). DHPS catalyzes the formation of dihydropteroate from para-aminobenzoic acid (PABA), a step that is absent in humans, making it a highly selective target for sulfonamide antibiotics (UniProt, P0AC14). DHFR follows this step by reducing dihydrofolate to tetrahydrofolate, the active form of folate required for one-carbon transfer reactions (PubMed, PMID: 15933018). While humans also possess DHFR, the bacterial version has a significantly different structure, allowing drugs like trimethoprim to bind with much higher affinity to the bacterial enzyme than the human isoform (PubChem, CID 5578). The therapeutic use of these targets typically involves a combination of a sulfonamide and a DHFR inhibitor, such as co-trimoxazole, to achieve a synergistic effect through sequential blockade of the pathway (NIH, LiverTox). This strategy effectively inhibits bacterial growth and is a cornerstone treatment for various infections, including urinary tract infections and Pneumocystis jirovecii pneumonia (Wikipedia, 2024). Resistance to these drugs often arises through mutations in the folP or folA genes, which encode DHPS and DHFR respectively, or through the acquisition of alternative enzyme variants (PubMed, PMID: 11585989).

Other names

Dihydropteroate synthaseDihydrofolate reductaseFolate synthesis enzymesFolPFolA7,8-dihydropteroate synthaseDHPSDHFR

Sequential inhibition of the bacterial folate biosynthetic pathway; sulfonamides act as antimetabolites that competitively inhibit dihydropteroate synthase (DHPS), while trimethoprim and pyrimethamine selectively inhibit bacterial dihydrofolate reductase (DHFR).