Description

In the mammalian host, dihydrofolate (https://pubchem.ncbi.nlm.nih.gov/compound/dihydrofolate) biosynthesis occurs via the reduction of folic acid (https://pubchem.ncbi.nlm.nih.gov/compound/folic%20acid), whereas in plasmodia (Plasmodium berghei, a malaria parasite) the biosynthesis of 7, 8-dihydropteroate (https://pubchem.ncbi.nlm.nih.gov/compound/7%2C8-dihydropteroate), an intermediate product in dihydrofolate (https://pubchem.ncbi.nlm.nih.gov/compound/dihydrofolate) synthesis, occurs via the enzymic catalysis of the reaction of 2-amino-4-hydroxy-6-hydroxymethyl-7, 8-dihydropteridine pyrophosphate with p-aminobenzoate (https://pubchem.ncbi.nlm.nih.gov/compound/p-aminobenzoate). Malaria parasites synthesize their folate (https://pubchem.ncbi.nlm.nih.gov/compound/folate) cofactors de novo and that the antimalarial action of sulfonamides is due to their inhibiting the plasmodial dihydropteroate (https://pubchem.ncbi.nlm.nih.gov/compound/dihydropteroate) synthesis. The enzymes 6-hydroxymethylpterin (https://pubchem.ncbi.nlm.nih.gov/compound/6-hydroxymethylpterin) pyrophosphokinase (EC 2. 7. 6. 3, HPPK) and dihydropteroate (https://pubchem.ncbi.nlm.nih.gov/compound/dihydropteroate) synthase (EC 2. 5. 1. 15, DHPS) catalyze sequential steps in folate (https://pubchem.ncbi.nlm.nih.gov/compound/folate) biosynthesis. They are present in microorganisms but absent in mammals and therefore are especially suitable targets for antimicrobials. Sulfa drugs (sulfonamides and sulfones) currently are used as antimicrobials targeting DHPS, although resistance to these drugs is increasing. A NADPH (https://pubchem.ncbi.nlm.nih.gov/compound/NADPH)-coupled microplate photometric assay could be used for rapid screening of chemical libraries for novel inhibitors of folate (https://pubchem.ncbi.nlm.nih.gov/compound/folate) biosynthesis as the first step in developing new antimicrobial drugs targeting the folate (https://pubchem.ncbi.nlm.nih.gov/compound/folate) biosynthetic pathway; in the microplate the product of the DHPS reaction, 7, 8-Dihydropteroic acid (https://pubchem.ncbi.nlm.nih.gov/compound/7%2C8-Dihydropteroic%20acid), is reduced to tetrahydropteroate (https://pubchem.ncbi.nlm.nih.gov/compound/tetrahydropteroate) by excess dihydrofolate (https://pubchem.ncbi.nlm.nih.gov/compound/dihydrofolate) reductase (DHFR) using the cofactor NADPH (https://pubchem.ncbi.nlm.nih.gov/compound/NADPH). (17134675, 4354403, 3546688).