Abstract
The mode of action of the tubulozole isomers, recently recognized as a new class of potential antimalarial agents, was investigated. Whereas neither glycolysis, protease activity, or nucleic acid biosynthesis was primarily affected, protein biosynthesis decreased soon after addition of the drug. Inhibitors of protein biosynthesis, however, did not show synergistic activity with tubulozole. Colcemid, on the other hand, had an effect on protein synthesis similar to that seen with the tubulozoles. Furthermore, combinations of the tubulozole isomers with compounds known to interact with tubulin inhibited malaria in a synergistic or antagonistic fashion. Therefore, the inhibition might be elicited by interaction with tubulin or some other component of the microtubules. This is remarkable insofar as only one of the tubulozole isomers affects mammalian cells by binding to tubulin.
Full text
PDF





Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Berenbaum M. C. A method for testing for synergy with any number of agents. J Infect Dis. 1978 Feb;137(2):122–130. doi: 10.1093/infdis/137.2.122. [DOI] [PubMed] [Google Scholar]
- Bowdon B. J., Waud W. R., Wheeler G. P., Hain R., Dansby L., Temple C., Jr Comparison of 1,2-dihydropyrido[3,4-b]pyrazines (1-deaza-7,8-dihydropteridines) with several other inhibitors of mitosis. Cancer Res. 1987 Mar 15;47(6):1621–1626. [PubMed] [Google Scholar]
- Delves C. J., Ridley R. G., Goman M., Holloway S. P., Hyde J. E., Scaife J. G. Cloning of a beta-tubulin gene from Plasmodium falciparum. Mol Microbiol. 1989 Nov;3(11):1511–1519. doi: 10.1111/j.1365-2958.1989.tb00137.x. [DOI] [PubMed] [Google Scholar]
- Dieckmann-Schuppert A., Franklin R. M. Compounds binding to cytoskeletal proteins are active against Plasmodium falciparum in vitro. Cell Biol Int Rep. 1989 May;13(5):411–418. doi: 10.1016/0309-1651(89)90135-5. [DOI] [PubMed] [Google Scholar]
- Divo A. A., Geary T. G., Jensen J. B., Ginsburg H. The mitochondrion of Plasmodium falciparum visualized by rhodamine 123 fluorescence. J Protozool. 1985 Aug;32(3):442–446. doi: 10.1111/j.1550-7408.1985.tb04041.x. [DOI] [PubMed] [Google Scholar]
- Divo A. A., Geary T. G., Jensen J. B. Oxygen- and time-dependent effects of antibiotics and selected mitochondrial inhibitors on Plasmodium falciparum in culture. Antimicrob Agents Chemother. 1985 Jan;27(1):21–27. doi: 10.1128/aac.27.1.21. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Geary T. G., Jensen J. B. Effects of antibiotics on Plasmodium falciparum in vitro. Am J Trop Med Hyg. 1983 Mar;32(2):221–225. doi: 10.4269/ajtmh.1983.32.221. [DOI] [PubMed] [Google Scholar]
- Geuens G. M., Nuydens R. M., Willebrords R. E., Van de Veire R. M., Goossens F., Dragonetti C. H., Mareel M. M., De Brabander M. J. Effects of tubulozole on the microtubule system of cells in culture and in vivo. Cancer Res. 1985 Feb;45(2):733–742. [PubMed] [Google Scholar]
- Ginsburg H., Nissani E., Krugliak M. Alkalinization of the food vacuole of malaria parasites by quinoline drugs and alkylamines is not correlated with their antimalarial activity. Biochem Pharmacol. 1989 Aug 15;38(16):2645–2654. doi: 10.1016/0006-2952(89)90550-9. [DOI] [PubMed] [Google Scholar]
- Holloway S. P., Sims P. F., Delves C. J., Scaife J. G., Hyde J. E. Isolation of alpha-tubulin genes from the human malaria parasite, Plasmodium falciparum: sequence analysis of alpha-tubulin. Mol Microbiol. 1989 Nov;3(11):1501–1510. doi: 10.1111/j.1365-2958.1989.tb00136.x. [DOI] [PubMed] [Google Scholar]
- Kiatfuengfoo R., Suthiphongchai T., Prapunwattana P., Yuthavong Y. Mitochondria as the site of action of tetracycline on Plasmodium falciparum. Mol Biochem Parasitol. 1989 May 1;34(2):109–115. doi: 10.1016/0166-6851(89)90002-9. [DOI] [PubMed] [Google Scholar]
- Lacey E., Edgar J. A., Culvenor C. C. Interaction of phomopsin A and related compounds with purified sheep brain tubulin. Biochem Pharmacol. 1987 Jul 1;36(13):2133–2138. doi: 10.1016/0006-2952(87)90141-9. [DOI] [PubMed] [Google Scholar]
- Lambros C., Vanderberg J. P. Synchronization of Plasmodium falciparum erythrocytic stages in culture. J Parasitol. 1979 Jun;65(3):418–420. [PubMed] [Google Scholar]
- Rinderknecht H., Geokas M. C., Silverman P., Haverback B. J. A new ultrasensitive method for the determination of proteolytic activity. Clin Chim Acta. 1968 Aug;21(2):197–203. doi: 10.1016/0009-8981(68)90127-7. [DOI] [PubMed] [Google Scholar]
- Sen K., Godson G. N. Isolation of alpha- and beta-tubulin genes of Plasmodium falciparum using a single oligonucleotide probe. Mol Biochem Parasitol. 1990 Mar;39(2):173–182. doi: 10.1016/0166-6851(90)90056-r. [DOI] [PubMed] [Google Scholar]
- Wesseling J. G., Dirks R., Smits M. A., Schoenmakers J. G. Nucleotide sequence and expression of a beta-tubulin gene from Plasmodium falciparum, a malarial parasite of man. Gene. 1989 Nov 30;83(2):301–309. doi: 10.1016/0378-1119(89)90116-9. [DOI] [PubMed] [Google Scholar]
- Wilson L., Friedkin M. The biochemical events of mitosis. I. Synthesis and properties of colchicine labeled with tritium in its acetyl moiety. Biochemistry. 1966 Jul;5(7):2463–2468. doi: 10.1021/bi00871a042. [DOI] [PubMed] [Google Scholar]
- Yayon A., Ginsburg H. Chloroquine inhibits the degradation of endocytic vesicles in human malaria parasites. Cell Biol Int Rep. 1983 Nov;7(11):895–895. doi: 10.1016/0309-1651(83)90207-2. [DOI] [PubMed] [Google Scholar]
- Zolg J. W., Macleod A. J., Scaife J. G., Beaudoin R. L. The accumulation of lactic acid and its influence on the growth of Plasmodium falciparum in synchronized cultures. In Vitro. 1984 Mar;20(3 Pt 1):205–215. doi: 10.1007/BF02618189. [DOI] [PubMed] [Google Scholar]