Abstract
The antifungal imidazoles miconazole and ketoconazole inhibit synthesis of essential cell membrane components. Furthermore, miconazole can exert direct physicochemical cell membrane damage at relatively high levels, but ketoconazole cannot. Experiments were designed to explain our previous observation that concentrations of miconazole capable of causing direct membrane damage were no more active against Candida albicans than equimolar levels of ketoconazole. When stationary-phase cells were inoculated into medium containing either drug at 3.8 X 10(-5) M, fungistatic effects were indistinguishable. If, however, such cultures were incubated 3 h before drug addition, differences were remarkable. After 3 h, miconazole caused a 99% reduction in CFU per milliliter within 20 min, but ketoconazole again was only fungistatic. The immediate onset, rapidity, and magnitude of the miconazole effect were indicative of direct lethal cell damage. Miconazole concentrations as low as 1.0 X 10(-5) M were similarly active. It was concluded that C. albicans undergoes phenotypic changes during the growth cycle that coincidentally confer susceptibility or resistance to the lethal direct membrane damage effect of miconazole. The fungistatic or metabolic effects of ketoconazole or low-level miconazole appeared to be independent of growth phase.
Full text
PDF


Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Beggs W. H. Comparison of miconazole- and ketoconazole-induced release of K+ from Candida species. J Antimicrob Chemother. 1983 Apr;11(4):381–383. doi: 10.1093/jac/11.4.381. [DOI] [PubMed] [Google Scholar]
- Cassone A., Kerridge D., Gale E. F. Ultrastructural changes in the cell wall of Candida albicans following cessation of growth and their possible relationship to the development of polyene resistance. J Gen Microbiol. 1979 Feb;110(2):339–349. doi: 10.1099/00221287-110-2-339. [DOI] [PubMed] [Google Scholar]
- Cope J. E. Mode of action of miconazole on Candida albicans: effect on growth, viability and K+ release. J Gen Microbiol. 1980 Jul;119(1):245–251. doi: 10.1099/00221287-119-1-245. [DOI] [PubMed] [Google Scholar]
- Cope J. E. The interaction of [3H]miconazole with Candida albicans. Sabouraudia. 1980 Sep;18(3):211–228. [PubMed] [Google Scholar]
- Daneshmend T. K., Warnock D. W. Clinical pharmacokinetics of systemic antifungal drugs. Clin Pharmacokinet. 1983 Jan-Feb;8(1):17–42. doi: 10.2165/00003088-198308010-00002. [DOI] [PubMed] [Google Scholar]
- Iwata K., Yamaguchi H., Hiratani T. Mode of action of clotrimazole. Sabouraudia. 1973 Jul;11(2):158–166. doi: 10.1080/00362177385190321. [DOI] [PubMed] [Google Scholar]
- Marriott M. S. Inhibition of sterol biosynthesis in Candida albicans by imidazole-containing antifungals. J Gen Microbiol. 1980 Mar;117(1):253–255. doi: 10.1099/00221287-117-1-253. [DOI] [PubMed] [Google Scholar]
- Sreedhara Swamy K. H., Sirsi M., Ramananda Rao G. R. Studies on the mechanism of action of miconazole: effect of miconazole on respiration and cell permeability of Candida albicans. Antimicrob Agents Chemother. 1974 Apr;5(4):420–425. doi: 10.1128/aac.5.4.420. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sud I. J., Chou D. L., Feingold D. S. Effect of free fatty acids on liposome susceptibility to imidazole antifungals. Antimicrob Agents Chemother. 1979 Nov;16(5):660–663. doi: 10.1128/aac.16.5.660. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sud I. J., Feingold D. S. Heterogeneity of action of mechanisms among antimycotic imidazoles. Antimicrob Agents Chemother. 1981 Jul;20(1):71–74. doi: 10.1128/aac.20.1.71. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sud I. J., Feingold D. S. Mechanisms of action of the antimycotic imidazoles. J Invest Dermatol. 1981 Jun;76(6):438–441. doi: 10.1111/1523-1747.ep12521036. [DOI] [PubMed] [Google Scholar]
- Van den Bossche H., Willemsens G., Cools W., Cornelissen F., Lauwers W. F., van Cutsem J. M. In vitro and in vivo effects of the antimycotic drug ketoconazole on sterol synthesis. Antimicrob Agents Chemother. 1980 Jun;17(6):922–928. doi: 10.1128/aac.17.6.922. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yamaguchi H., Iwata K. Effect of fatty acyl group and sterol composition on sensitivity of lecithin liposomes to imidazole antimycotics. Antimicrob Agents Chemother. 1979 May;15(5):706–711. doi: 10.1128/aac.15.5.706. [DOI] [PMC free article] [PubMed] [Google Scholar]
- van den Bossche H., Willemsens G., Cools W., Lauwers W. F., Le Jeune L. Biochemical effects of miconazole on fungi. II. Inhibition of ergosterol biosynthesis in Candida albicans. Chem Biol Interact. 1978 Apr;21(1):59–78. doi: 10.1016/0009-2797(78)90068-6. [DOI] [PubMed] [Google Scholar]