Dihydrofolate Reductase Inhibitors

Dihydrofolate reductase reduces 7,8-dihydrofolate to 5,6,7,8-tetrahydrofolate using NADPH - the single step of that sub-pathway. It is the key enzyme of folate metabolism, catalysing a reaction essential for de novo glycine and purine synthesis and for DNA precursor synthesis, and contributing to nuclear and mitochondrial de novo thymidylate biosynthesis. Drugs in this class inhibit that enzyme, so the target cell loses its supply of reduced folate and of the nucleotides built from it. The enzyme is present in both host and microbe: UniProt carries the human DHFR and the Escherichia coli folA entries, and records E. coli strains resistant to trimethoprim and to methotrexate. As MED-RT populates the class its members are the antifolate cytotoxics and antiprotozoals - methotrexate, pemetrexed, pralatrexate, trimetrexate, proguanil and lamotrigine; trimethoprim and pyrimethamine are filed one level up, in Folic Acid Metabolism Inhibitors. FDA's veterinary antimicrobial ranking gives the row 'sulfonamides, dihydrofolate reductase inhibitors, and combinations' two rankings, not one: critically important, because trimethoprim-sulfamethoxazole is one of limited available therapies for serious infections due to Nocardia species and Listeria monocytogenes, and important for sulfonamides alone, which are used to treat non-serious infections for which drugs from more than a few antimicrobial classes are available.