Inhibition studies of sulfonamide-containing folate analogs in yeast

Patel, O; Satchell, J; Baell, J; Fernley, R; Coloe, P; Macreadie, I

Author(s): Patel, O; Satchell, J; Baell, J; Fernley, R; Coloe, P; Macreadie, I;
Details: Publication Year 2003-01,Volume 9,Issue #2,Page 139-146
Journal Title: MICROBIAL DRUG RESISTANCE-MECHANISMS EPIDEMIOLOGY AND DISEASE
Publication Type: Journal Article
Abstract: 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.
Publisher: MARY ANN LIEBERT INC PUBL
Keywords: SACCHAROMYCES-CEREVISIAE; DIHYDROPTEROATE SYNTHASE; DIHYDROFOLATE-REDUCTASE; DRUG; METHOTREXATE; RESISTANCE
Publisher's Version: https://doi.org/10.1089/107662903765826723
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2003-01-01 12:00:00