Dihydropteroate Synthase (Sulfonamides) and Dihydrofolate Reductase Inhibitors

Sulfa drugs and trimethoprim-like agents are inhibitors of two enzymes involved in the synthesis of tetrahydrofolate (THF): dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR), respectively. These drugs are antimetabolites, as THF is involved in a host of biosynthetic processes (purines, amino acids, etc.). DHPS inhibitors have been designed since the 1940s using sulfanilamide, an isostructural compound with p-amino benzoic acid, a substrate of the enzyme. DHFR inhibitors – among which trimethoprim is the best-known agent – using the pteridine moiety of dihydrofolate for binding to the enzyme, were obtained from the 1960s onwards. Although these two agents are efficient as antibacterials (especially in combination), there is significant bacterial resistance to both sulfa drugs and DHFR inhibitors. This drug resistance can be understood at the molecular level using high-resolution X-ray crystallography of the enzyme-substrate/inhibitor adducts for both enzymes. Such studies may assist the design of new inhibitor drugs, which may circumvent the resistance problems, although this currently remains an unattained goal.