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Growth phase in relation to ketoconazole and miconazole susceptibilities of Candida albicans
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.
Insights
Miconazole and ketoconazole are antifungals that target cell membranes. Miconazole, but not ketoconazole, causes direct cell damage, with effectiveness varying based on Candida albicans growth phase.
Area of Science:
- Mycology
- Pharmacology
- Cell Biology
Background:
- Antifungal imidazoles miconazole and ketoconazole inhibit cell membrane synthesis.
- Miconazole can cause direct physicochemical cell membrane damage, unlike ketoconazole.
- Previous observations showed similar activity of miconazole and ketoconazole against Candida albicans at high concentrations.
Purpose of the Study:
- To investigate why miconazole concentrations causing direct membrane damage were not more active than ketoconazole.
- To elucidate the mechanisms behind the differential activity of miconazole and ketoconazole against Candida albicans.
Main Methods:
- Comparing the fungistatic and fungicidal effects of miconazole and ketoconazole against Candida albicans.
- Investigating the impact of cell growth phase on the susceptibility to antifungal drugs.
- Utilizing colony-forming unit (CFU) counts to quantify drug efficacy.
Main Results:
- At 3.8 X 10(-5) M, both drugs showed indistinguishable fungistatic effects on stationary-phase Candida albicans.
- When added after a 3-hour incubation, miconazole rapidly reduced CFU by 99% within 20 minutes, indicating lethal damage.
- Ketoconazole consistently exhibited only fungistatic effects, regardless of incubation time or growth phase.
Conclusions:
- Candida albicans exhibits phenotypic changes during its growth cycle, influencing susceptibility to miconazole's direct membrane damage.
- The fungistatic effects of ketoconazole and low-level miconazole are independent of the fungal growth phase.
- Miconazole's potent fungicidal activity is linked to direct membrane damage, which is dependent on the cell's growth-related characteristics.