MECHANISM FOR SYNERGISM BETWEEN SULFONAMIDES AND TRIMETHOPRIM CLARIFIED

Pseudomonas aeruginosa, Escherichia coli, Pseudomonas cepacia and Mora xella catarrhalis were selected for their markedly different resistanc e patterns to sulphonamides and trimethoprim. In addition, strains of E. coli and P. cepacia were selected having different resistance profi les to the inhibition of dihydropteroate synthetase and dihydrofolate reductase. All inhibitors of dihydropteroate synthetase combined in an y combination with inhibitors of dihydrofolate reductase resulted in m utual enhancement of bacterial uptakes of the inhibitors and correspon ding increased antibacterial activity of the combinations. High concen trations of sulphonamides or p-aminobenzoic acid plus trimethoprim cau sed a decrease in overall activity of the combination and indicated th at both sulphonamides and p-aminobenzoic acid at high concentrations c an interact with dihydrofolate reductase. The antibacterial activity o f p-aminobenzoic acid at high concentrations is considered to be a blo cking effect on dihydrofolate reductase even though p-aminobenzoic aci d at low concentrations is an essential part of the synthesis of dihyd rofolic acid. These findings support an alternative hypothesis for the mechanism of antibacterial action of individual antifolates and their mechanism of synergism in combination.