Antibacterial Agents 5. Antimetabolites and Synthetic Drugs

  • David Edwards
Chapter

Abstract

Antimetabolite chemotherapy came of age when Woods in 1940 demonstrated that the sulphonamide sulphanilamide competed with PABA for the enzyme responsible for folate synthesis in bacteria. This was a key discovery because it opened the way to chemotherapy based on the synthesis of molecules which were structural and functional analogues of key metabolites of the cell. Generally, chemotherapy based on antimetabolites has not been the success it was initially envisaged, since antimetabolites, which proved good inhibitors of bacterial growth in vitro, failed to perform as expected in vivo. The reasons for this are many and include the fact that since most of them are competitive inhibitors of a cell reaction the inhibition causes the substrate of the inhibited enzyme to build up until concentrations are reached which overcome the block. A second, equally important, feature of antimetabolites is that for the most part they are small highly soluble molecules which are eliminated from the blood very rapidly, making it difficult to achieve prolonged and adequate blood levels necessary for the therapeutic effect.

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10.10 References and Further Reading

  1. Baines, E. J. (1977). Metronidazole: sixteen years of developments. In Metronidazole (S. Finegold, ed.). Excerpta Medica, Amsterdam, pp. 61–71Google Scholar
  2. Barbosa, J. C. and Ferrelra, I. (1978). Sulphadoxins-pyrimethamine (Fansidor) in pregnant women with Toxoplasma antibody titres. Curr. Chemother., 1, 134–5Google Scholar
  3. Brown, G. M. (1962). The biosynthesis of folic acid: inhibition by sulphonamides. J. biol. Chem., 237, 536–42Google Scholar
  4. Chao, L. (1978). An unusual interaction between the target of nalidixic acid and novobiocin. Nature, Lond., 271, 385–6CrossRefGoogle Scholar
  5. Chatterjee, S. N., Ghose, S. and Maiti, M. (1977). Cross-linking of deoxyribonucleic acid in furazolidone treated Vibrio cholerae cells. Biochem. Pharmacol., 26, 1453–4CrossRefGoogle Scholar
  6. Chatterjee, S. N., Maiti, M. and Ghose, S. (1975). Interaction of furazolidone with DNA. Biochim. biophys. Acta, 402, 161–5CrossRefGoogle Scholar
  7. Cossarelli, N. R. (1977). The mechanism of action of inhibitors of DNA synthesis. A. Rev. Biochem., 46, 641–68CrossRefGoogle Scholar
  8. Edwards, D. I. (1977). The action of metronidazole on DNA. J. antimicrobial Chemother., 3, 43–8CrossRefGoogle Scholar
  9. Edwards, D. I. (1979). Cancer chemotherapy-new approaches. In Companion to the Life Sciences, Vol. 2 (S. Day, ed.). Van Nostrand-Rheinhold, New York (in press).Google Scholar
  10. Edwards, D. I. and Mathison, G. E. The mode of action of metronidazole against Trichomonas vaginalis. J. gen. Microbiol, 63, 297–302Google Scholar
  11. Edwards, D. I. and Schoolar, A. I. (1971). Inhibition of sugar synthesis and potentiation of chlorophyll degradation in sugar can leaf tissue by metronidazole. Z. Pflanzenphysiol., 64, 73–6Google Scholar
  12. Edwards, D. I., Dye, M.and Carne, H. (1973). The selective toxicity of antimicrobial nitroheterocyclic drugs. J. gen. Microbiol., 76, 135–145CrossRefGoogle Scholar
  13. Edwards, D. I., Knight, R. C. and Kantor, I. M. (1978). Interaction of nitroimidazole drugs with DNA. Curr. Chemother., 1, 714–7Google Scholar
  14. Edwards, D. I., Mathison, G. E. and Platt, D. J. (1974). Metronidazole-an antimicrobial drug which inhibits photosynthesis. Z. Pflanzenphysiol., 71, 424–7CrossRefGoogle Scholar
  15. Ferone, R., Burchall, J. J. and Hitchings, G. H. (1969). Plasmodium berghei dihydrofolate reductase: isolation properties, and inhibition by antifolates. Mol. Pharmacol., 5, 49–54Google Scholar
  16. Ferone, R., O’Shea, M. and Yoeli, M. (1970). Altered dihydrofolate reductase associated with drug resistance transfer between rodent plasmodia. Science, N.Y., 167, 1263–6CrossRefGoogle Scholar
  17. Finegold, S. M. (1977). In Metronidazole. (S. M. Finegold ed.), Excerpta Medica, Amsterdam, pp. 426–35Google Scholar
  18. Flockhart, I. R., Large, P., Troup, D., Malcolm, S. L. and Marten, T. R. (1978). Pharmacokinetic and metabolic studies of the hypoxic cell radiosensitiser misonidazole. Xenobiotica, 8, 97–105CrossRefGoogle Scholar
  19. Forbes, M., Peets, E. A. and Kuck, N. A. (1966). Effect of ethambutol on mycobacteria. Ann. N.Y. Acad. Sci., 135, 726–33CrossRefGoogle Scholar
  20. Herrlich, P. and Schweiger, M. (1976). Nitrofurans, a group of synthetic antibiotics with a new mode of action; discrimination of specific messenger RNA classes. Proc. nat. Acad. Sci. U.S.A., 73, 3386–90CrossRefGoogle Scholar
  21. Hitchings, G. H. and Burchall, J. J. (1965). Inhibition of folate biosynthesis and function as a basis for chemotherapy. Adv. Enzymol., 27, 418–68Google Scholar
  22. Hoffman, R. K. (1971). Toxic gases. In Inhibition and Destruction of the Microbial Cell (W. B. Hugo, ed.). Academic Press, London, pp. 244–6Google Scholar
  23. Ings, R. M. J., McFadzean, J. A. and Ormerod, W. E. (1974). The mode of action of metronidazole in Trichomonas vaginalis and other micro-organisms. Biochem. Pharmacol., 23, 1421–9CrossRefGoogle Scholar
  24. Kerry, D. W., Hamilton-Miller, J. M. T. and Brumfit, W. (1975). Trimethoprim and rifampicin in vitro activities separately and in combination. J. antimicrob. Chemother., 1, 417–27CrossRefGoogle Scholar
  25. Knight, R. C., Skolimowski, I. M. and Edwards, D. I. (1978). Effect of reduced metronidazole on DNA. Biochem. Phrmacol., 27, 2089–93CrossRefGoogle Scholar
  26. Knight, R. C., Rowley, D. A., Skolimowski, I. M. and Edwards, D. I. (1979). Mode of action of nitroimidazole antimicrobial and tumour radiosensitizing drugs: effect of electrolytically reduced misonidazole on DNA. Int. J. Radiat. Biol. (in press)Google Scholar
  27. McCalla, D. R. (1979). Nitrofurans. In Antibiotics, Vol. V (O. Hahn, ed.). Springer-Verlag, Berlin, Heidelberg, New YorkGoogle Scholar
  28. McCalla, D. R., Reuvers, A. and Kaiser, C. (1971). Breakage of bacterial DNA by nitrofuran derivatives. Cancer Res., 31, 2184–8Google Scholar
  29. Mitchison, D. A., Grosset, J., Aquinas, S. M., Tripathy, S. P., Darbyshire, J. and Friedlin, A. G. (1978). Chemotherapy of tuberculosis. Curr. Chemother., 1, 43–7Google Scholar
  30. Muller, M., Lindmark, D. G. and McLaughlin, J. (1976). Mode of action of nitroimidazoles on trichomonads. In Biochemistry of Parasites and Host-Parasite Relationships (H. Van den Bossche, ed.). North-Holland, Amsterdam, pp. 537–44Google Scholar
  31. Plant, C. W. and Edwards, D. I. (1976). The effect of tinidazole, metronidazole and nitrofurazone on nucleic acid synthesis in Clostridium bifermentans. J. antimicrobial Chemother., 2, 203–9CrossRefGoogle Scholar
  32. Ramareddy, G. and Reiter, H. (1969). Specific loss of newly replicated deoxyribonucleic acid in naladixic treated Bacillus subtilis 168. J. Bact., 100, 724–9Google Scholar
  33. Richey, D. P. and Brown, G. M. (1969). The biosynthesis of folic acid: purification and properties of the enzymes required for the formation of dihydropteroic acid. J. biol. Chem., 244, 1582–92Google Scholar
  34. Rosenkranz, H. J. and Speck, W. T. (1977). Studies on the significance of the mutagenicity of metronidazole for Salmonella typhimurium. In Metronidazole (S. Finegold, ed.). Excerpta Medica, Amsterdam, pp. 119–25Google Scholar
  35. Shepherd, R. C. (1965). Synthetic antibacterial agents. A. Repts. med. Chem., pp. 118–28Google Scholar
  36. Sims, P. and Gutteridge, W. E. (1976). Biochemical effect and mode of action of a 5-nitrofuran drug, SQ 18506, on Trypanosoma cruzi. In Biochemistry of Parasites and Host-Parasite Relationships (H. Van den Bossche, ed.). North-Holland, Amsterdam, pp. 485–91Google Scholar
  37. Tu, Y. and McCalla, D. R. (1975). Effect of activated nitrofurans on DNA. Biochim. biophys. Acta., 402, 142–9CrossRefGoogle Scholar
  38. Tu, Y. and McCalla, D. R. (1976). Effect of nitrofurazone on bacterial RNA and ribosome synthesis and on the function of ribosomes. Chem. biol. Interact., 14, 81–91CrossRefGoogle Scholar
  39. Wardman, P. (1977). The use of nitro-aromatic compounds as hypoxic cell radio-sensitisers. Curr. Topics Radiat. Res. Qtly., 11, 347–98Google Scholar
  40. Whillet, T. D., Hugo, W. B. and Wilkinson, G. R. (1965). Sterilization and Disinfection. Heinemann, LondonGoogle Scholar
  41. Winder, F. G., Brennan, P. J. and McDonell, I. (1967). Effects of isoniazid on the composition of mycobacteria, with particular reference to soluble carbohydrates and related substances. Biochem. J., 104, 385–93CrossRefGoogle Scholar
  42. Winshell, E. B. and Rosenkranz, H. S. (1970). Naladixic acid and the metabolism of Escherichia coli. J. Bact., 104, 1168–75Google Scholar
  43. Wolf, B. and Hotchkiss, R. D. (1963). Genetically modified folic acid synthesizing enzymes of Pneumococcus. Biochemistry, 2, 145–50CrossRefGoogle Scholar
  44. Woods, D. D. (1962). The biochemical mode of action of the sulphonamides. J. gen. Microbiol., 29, 687–702CrossRefGoogle Scholar
  45. Youatt, J. (1969). A review of the action of isoniazid. Am. Rev. res. Dis., 99, 729–56Google Scholar

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© David Edwards 1980

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  • David Edwards

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