Mechanism for Synergism between Sulphonamides and Trimethoprim Clarified

Abstract

Pseudomonas aeruginosa, Escherichia coli, Pseudomonas cepacia and Moraxella catarrhalis were selected for their markedly different resistance patterns to sulphonamides and trimethoprim. In addition, strains of E. coli and P. cepacia were selected having different resistance profiles to the inhibition of dihydropteroate synthetase and dihydrofolate reductase. All inhibitors of dihydropteroate synthetase combined in any combination with inhibitors of dihydrofolate reductase resulted in mutual enhancement of bacterial uptakes of the inhibitors and corresponding increased antibacterial activity of the combinations. High concentrations of sulphonamides or p-aminobenzoic acid plus trimethoprim caused a decrease in overall activity of the combination and indicated that both sulphonamides and p-aminobenzoic acid at high concentrations can interact with dihydrofolate reductase. The antibacterial activity of p-aminobenzoic acid at high concentrations is considered to be a blocking effect on dihydrofolate reductase even though p-aminobenzoic acid at low concentrations is an essential part of the synthesis of dihydrofolic acid. These findings support an alternative hypothesis for the mechanism of antibacterial action of individual antifolates and their mechanism of synergism in combination.

Mechanism of the antimicrobial drug trimethoprim revisited

“…4) showed that the pABGlu portion, i.e., 57.1% (Fig. 4, inset), consisted mainly of pABA-polyglutamates (5)(6)(7)(8). (Chromatography of conjugase-treated or untreated control samples showed that less than 5% of the radiolabel had eluted under the same conditions; results not shown.)…”

“…E. coli strain NCIMB 8879 (7) was purchased as a lyophilized vial from the National Center for Industrial and Marine Bacteria, Aberdeen, Scotland. Trimethoprim (Monotrim, BP 20 mg/ml) was from Solvay Healthcare, Southampton, U.K. Columbia agar (Lab M, Bury, U.K.) supplemented with 7% horse blood was prepared by the Microbiology Department, St. James's Hospital, Ireland.…”

Comparison of Fractional Inhibitory Concentration Index with Response Surface Modeling for Characterization of In Vitro Interaction of Antifungals against Itraconazole-Susceptible and -Resistant Aspergillus fumigatus Isolates

“…TB on the other hand inhibits the action of squalene epoxidase, a crucial enzyme in the formation of ergosterol (6). Thus, this is another example of synergism between two drugs that block different steps of the same pathway, similar to the combination of trimethoprim with sulfonamides (19).…”

Study of Chemical Composition of Garlic Oil and Comparative Analysis of Co Trimoxazole in Response to in Vitro Antibacterial Activity

“…A synergy effect between the 2 drugs has been demonstrated both in vitro and in most studies. 10 The two agents are synergistic in inhibition of folate synthesis -the sulfamethoxazole inhibiting production of dihydrofolate from para-aminobenzoic acid and the trimethoprim inhibiting the next step in the pathway from dihydrofolate to tetrahydrofolate. In this study, selected brands of Co-trimoxazole tablets sourced from pharma stores of Vidisha were chemically evaluated.…”