Inhibition studies of sulfonamide-containing folate analogs in yeast.
In the folate biosynthetic pathway, sulfa drugs (sulfonamides and sulfones) compete with the natural substrate, para-aminobenzoate (pABA) causing depletion of dihydrofolate (DHF) and subsequent growth inhibition. The sulfa drugs condense with 2-amino-4-hydroxy-6-hydroxymethyl-7,8 dihydropteridine pyrophosphate (DHPPP) forming sulfa-dihydropteroate (sulfa-DHP). Here evidence is presented using yeast that such dihydropteroate (DHP) analogs are inhibitory through competition with DHF. Two folate synthesis mutants, with respective dihydrofolate synthase (DHFS) and dihydropteroate synthase (DHPS) deletions and requiring DHF for growth were exposed to sulfa drugs. The DHFS knockout mutant was inhibited, but the DHPS knockout mutant that was incapable of forming sulfa-DHP was insensitive. Such sulfa-DHP compounds were chemically synthesized and shown to be inhibitory in vivo by competing with DHF, but in vitro assays with double the concentration of the sulfa-DHP to DHF showed no inhibition of dihydrofolate reductase (DHFR). Sequence analysis of resistant mutants obtained in the presence of sulfa drugs showed no changes in DHFR, or DHPS, unlike previously found antifolate-resistant mutants. The diamino derivatives, which are precursors of the sulfa-DHP, were found to be DHFR inhibitors. These results suggest that a new class of drugs, based on DHP analogs, could be investigated.
Patel
Onisha
O
CSIRO Health Sciences and Nutrition & Biomolecular Research Institute, Parkville, Victoria, Australia.
Satchell
Jacqueline
J
Baell
Jonathan
J
Fernley
Ross
R
Coloe
Peter
P
Macreadie
Ian
I
D000890:Anti-Infective Agents / Q000378:metabolism / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D004094:Dihydropteroate Synthase / Q000235:genetics / Q000378:metabolism; D005492:Folic Acid / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology*; D017353:Gene Deletion; D009154:Mutation / Q000235:genetics; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D010453:Peptide Synthases / Q000235:genetics / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000378:metabolism*; D013449:Sulfonamides / Q000378:metabolism / Q000494:pharmacology*; D013450:Sulfones / Q000378:metabolism
D000890:Anti-Infective Agents; D010880:Piperidines; D013449:Sulfonamides; D013450:Sulfones; C050328:3-(3,4-dihydroxyphenyl)-N-n-propylpiperidine; D009249:NADP; D005492:Folic Acid; D004094:Dihydropteroate Synthase; D010453:Peptide Synthases; C020041:dihydrofolate synthetase