Hostname: page-component-77c89778f8-n9wrp Total loading time: 0 Render date: 2024-07-18T20:30:54.087Z Has data issue: false hasContentIssue false

Inhibition by pyrimidine analogues of the synthesis of folic acid by trachoma agents

Published online by Cambridge University Press:  15 May 2009

P. Reeve
Affiliation:
M.R.C. Trachoma Research Unit, Lister Institute of Preventive Medicine, London, S. W. 1
Janice Taverne
Affiliation:
M.R.C. Trachoma Research Unit, Lister Institute of Preventive Medicine, London, S. W. 1
S. R. M. Bushby
Affiliation:
Wellcome Research Laboratories, Beckenham, Kent
Rights & Permissions [Opens in a new window]

Summary

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

Trimethoprim, a 2,4-diaminopyrimidine derivative which inhibits the growth of some bacteria by interfering with folic acid synthesis, inhibited the growth of several strains of the trachoma agent. Inhibition was most clearly demonstrated by measuring prolongation of mean death time of groups of chick embryos inoculated with a single lethal dose of agent. Over a certain range, prolongation was proportional to the logarithm of concentration of inhibitor; higher concentrations were toxic for the embryo. On a weight basis, trimethoprim was not as active as sulphafurazole. Inoculation in conjunction with sulphafurazole resulted in slight potentiation of activity. A related pyrimidine derivative, the antimalarial drug pyrimethamine, also significantly inhibited the growth of one strain of trachoma.

In cell culture, trimethoprim decreased the number of inclusions formed by a suspension of the trachoma agent and induced morphological changes in the inclusions similar to those caused by sulphafurazole.

Inhibition of the growth of the trachoma agent in the chick embryo was reversed by leucovorin calcium. It is concluded that, as with bacteria, the drug acts by blocking the folio acid cycle and that the trachoma agent most probably contains a dihydrofolate reductase.

Type
Original Articles
Copyright
Copyright © Cambridge University Press 1968

References

Burchall, J. J. & Hitchings, G. H. (1965). Inhibitor binding analysis of dihydrofolate reductases from various species. Molec. Pharmacol. 1, 126.Google Scholar
Bushby, S. R. M. & Barnett, M. (1967). Trimethoprim-sulphonamides—in vitro sensitivity of 384 strains of bacteria. Proceedings 5th International Congress of Chemotherapy, Vienna, June 25–July 2, 1967. A 1–6/11, 753.Google Scholar
Bushby, S. R. M. & Hitchings, G. H. (1968). Trimethoprim, a sulphonamide potentiator. Br. J. Pharmac. Chemother. (in the Press).Google Scholar
Clarke, M. L. (1962). A mixture of diaveridine and sulphaquinoxaline as a coccidiostat for poultry. I. Preliminary studies on efficiency against Eimeria tenella and E. necatrix infections, and on toxicity in poultry. Vet. Rec. 74, 845.Google Scholar
Collier, L. H. & Sowa, J. (1958). Isolation of trachoma virus in embryonate eggs. Lancet i, 993.CrossRefGoogle Scholar
Cooper, R. G. & Wald, M. (1964). Successful treatment of Proteus septicaemia with a new drug, Trimethoprim. Med. J. Aust. ii, 93.Google Scholar
Czonka, G. J. (1967). Therapeutic trial of trimethoprim as a potentiator of sulphonamides in gonorrhoea. Br. J. vener. Dis. 43, 161.Google Scholar
Drew, C. D. M., Hughes, D. T. D., Fowls, A. S. E. & Cassell, M. A. (1967). Effective treatment of chronic bronchitis with short-term trimethoprim and sulphamethoxazole. Proceedings, 5th International Congress of Chemotherapy, Vienna, June 25–July 2, 1967, A l–5a/3, 293.Google Scholar
Drew, C. D. M., Hughes, D. T. D. & Jenkins, G. C. (1967). Long-term treatment of chest infections with a combination of trimethoprim and a sulphonamide. A study of the clinical, bacteriological and haematological effects. Proceedings, 5th International Congress of Chemotherapy, Vienna, June 25–July 2, 1967 (in the Press).Google Scholar
Dulbecco, R. & Vogt, M. (1954). Plaque formation and isolation of pure lines with poliomyelitis virus. J. exp. Med. 99, 167.Google Scholar
Eyles, D. E. & Coleman, N. (1953). Synergistic effect of sulfadiazine and Daraprim against experimental toxoplasmosis in the mouse. Antibiotics Chemother. 3, 483.Google ScholarPubMed
Furness, G., Graham, D. M. & Reeve, P. (1960). The titration of trachoma and inclusion blennorrhoea viruses in cell cultures. J. gen. Microbiol. 23, 613.Google Scholar
Gear, J. H. S., Gordon, F. B., Jones, B. R. & Bell, S. D. Jun. (1963). Nomenclature of isolates of virus from trachoma and inclusion blennorrhoea. Nature, Lond. 197, 26.Google Scholar
Graham, D. M. (1965). Growth and neutralization of the trachoma agent in mouse lung. Nature, Lond. 207, 1379.Google Scholar
Hitchings, G. H. & Burchall, J. J. (1965). Species differences among dihydrofolate reductases. Fedn Proc. Fedn Am. Socs exp. Biol. 25 (Part 1), 881.Google Scholar
Jones, B. R. (1961). TRIC virus infections in London. Trans, ophthal. Soc. U.K. 81, 367.Google Scholar
Lin, H. S. & Moulder, J. W. (1966). Patterns of response to sulfadiazine, D-cycloserine, and D-alanine in members of the psittacosis group. J. infect. Dis. 116, 372.Google Scholar
Moulder, J. W. (1964). The psittacosis group as bacteria. Ciba Lect. microb. Biochem.Google Scholar
Murray, E. S., Bell, S. D., Hanna, A. T., Nicholls, R. L. & Snyder, J. C. (1960). Studies on trachoma. 1. Isolation and identification of strains of elementary bodies from Saudi Arabia and Egypt. Am. J. trop. Med. Hyg. 9, 116.CrossRefGoogle ScholarPubMed
Noall, E. W. P., Sewards, H. F. G. & Waterworth, P. M. (1962). Successful treatment of a case of Proteus septicaemia. Br. med. J. ii, 1101.Google Scholar
Rollo, I. M. (1955). The mode of action of sulphonamides, proguanil and pyrimethamine on Plasmodium gallinaceum. Br. J. Pharmac. Chemother. 10, 208.CrossRefGoogle ScholarPubMed
T'Ang, F. F., Chang, H. L., Huang, Y. T. & Wang, K. C. (1957). Studies on the etiology of trachoma with special reference to the isolation of the virus in chick embryos. Chin. med. J. 75, 49.Google Scholar
Taverne, J., Blyth, W. A. & Reeve, P. (1964 a). Toxicity of the agents of trachoma and inclusion conjunctivitis. J. gen. Microbiol. 37, 271.Google Scholar
Taverne, J., Blyth, W. A. & Reeve, P. (1964 b). Growth in the chick embryo of strains of trachoma and inclusion blennorrhoea virus of differing virulence. J. gen. Microbiol. 37, 277.CrossRefGoogle ScholarPubMed