Evolution of the bacterial dihydrofolate reductase inhibitors.

(1991). Effect of ampicillin-sulbactam on human polymorphnuclear leukocyte function. (1990). Effect of azithromycin, roxithromycin and erythromycin on human polymorphnuclear leukocyte function against Staphylococcus aureus.induced modification of the kinetics of growth of Gram-negative bacteria and susceptibility to phagocytic killing by human neutrophils. (1979). Effects of subminimal inhibitory concentrations of ampicillin, chloramphenicol, and nitrofluantoin on the attachment of Escherichia coli to human uroepithelial cells in vitro. (1994). Postantibiotic effect of roxithromycin on streptolysin O production, hydrophobicity and bactericidal activity of PMNL by Streptococcus pyogenes. (1992). Effect of macrolides on ultrastructure of Staphylococcus aureus during postantibiotic phase. Numerous pyrimidine and purine analogues were synthesized in the late 1940s as potential nucleic acid antagonists. Particular interest was devoted to antagonists of thymine. It was quickly realized that the 2,4-diaminopytimi-dines inhibit folic acid utilization and that this was a general property of all of these compounds (Hitchings et al., 1950; Hitchings, 1989). It was recognised that the 3,4,5-trimethoxyl-diaminopyrimidine-derivative was outstanding for its breadth of antibacterial activity. Consequently it was selected for detailed study and clinical trials in 1959 (Roth et al., 1962) and given the name trimethoprim. Subsequently a 3,4-dimethoxy-5-bromo derivative was also found to be active. The role of bromine substitution on the benzyl-ring of trimethoprim was later confirmed with an analogue in which the 4-methoxy group, instead of being in the 5 position, was substituted by this halogen; the compound was synthesized in 1972 (Kompis et al., 1980) and named brodimoprim. The effect of this substitution was to improve the trimethoprim binding to bacterial DHFR (Then & Hermann, 1984), providing equivalent or better antibacterial activity, improving lipid solubility and the pharmacokinetic behaviour, and to achieve sufficiently high concentrations at the infection site (Weidekamm, 1993). Trimethoprim was put forward as a potentia-tor of sulphonamides for the treatment of bacterial infections: sulphamethoxazole was chosen as the sulphonamide owing matched half-life of trimethoprim. It was argued that the combination of sulphamethoxazole and trimethoprim, later given the name co-trimoxa-zole in Europe, offered several antimicrobial advantages (Hitchings, 1989). Since its introduction in 1968 co-trimoxazole is still widely used for the treatment of a wide variety of bacterial infections, toxoplasmosis and in particular Pneumocystis carinii pneumonia. However, in many circumstances, it is the trimethoprim moiety of this combination that is responsible for its clinical effectiveness owing to increasing bacterial resistance to the sulphonamide. In fact, the sulphonamide moiety of the mixture may be disadvantageous because of a number of …