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Mechanism for synergism between sulphonamides and trimethoprim clarified
R M Richards1, R B Taylor, Z Y Zhu
1School of Pharmacy, Robert Gordon University, Schoolhill, Aberdeen, UK.
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.
Insights
Combining sulphonamides and trimethoprim enhances antibacterial activity by increasing drug uptake. High concentrations can inhibit dihydrofolate reductase, revealing new insights into antifolate drug mechanisms.
Area of Science:
- Microbiology
- Pharmacology
- Biochemistry
Background:
- Sulphonamides and trimethoprim are antibiotics targeting the folic acid pathway.
- Understanding their synergistic mechanisms and resistance patterns is crucial for effective treatment.
Purpose of the Study:
- To investigate the synergistic antibacterial activity of sulphonamides and trimethoprim against various bacterial strains.
- To explore the impact of drug concentration on the inhibition of dihydropteroate synthetase and dihydrofolate reductase.
Main Methods:
- Utilized bacterial strains with distinct resistance profiles: Pseudomonas aeruginosa, Escherichia coli, Pseudomonas cepacia, and Moraxella catarrhalis.
- Assessed the combined effects of dihydropteroate synthetase and dihydrofolate reductase inhibitors on bacterial uptake and antibacterial activity.
- Investigated high-concentration effects of sulphonamides and p-aminobenzoic acid in combination with trimethoprim.
Main Results:
- Combinations of dihydropteroate synthetase and dihydrofolate reductase inhibitors showed mutual enhancement in bacterial uptake and activity.
- High concentrations of sulphonamides or p-aminobenzoic acid with trimethoprim decreased overall activity.
- Evidence suggests high concentrations of sulphonamides and p-aminobenzoic acid interact with dihydrofolate reductase.
Conclusions:
- Findings support an alternative hypothesis for the antibacterial action of individual antifolates.
- The study elucidates the complex mechanisms underlying the synergism of antifolate drug combinations.
- High concentrations of p-aminobenzoic acid exhibit a blocking effect on dihydrofolate reductase, distinct from its role at low concentrations.