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Requirement for nonprotonated drug molecules in the direct lethal action of miconazole against Candida albicans
1General Medical Research Service, Veterans Administration Medical Center, Minneapolis, MN 55417.
Abstract:
At greater than or equal to 10(-5) M, miconazole (MCZ) can exert a direct physicochemical cell-damaging lethal action against logarithmic phase yeasts of Candida albicans. The imidazole moiety of MCZ has a pKa approximately 6.5. Thus, in media of pH greater than 6.5 most drug molecules are nonprotonated (MCZ degrees). Conversely, at pH less than 6.5 the majority are protonated and carry a positive charge (MCZH+). Our earlier work suggesting that MCZ degrees is required for direct lethal action was tested further. In support of such a requirement, we established a minimal lethal concentration of MCZ degrees (i.e. 5 x 10(-6) M) that was relatively independent of pH, MCZ concentration, and MCZ degrees:MCZH+ ratio.
Insights
Miconazole (MCZ) directly damages Candida albicans cells at high concentrations. The non-protonated form of MCZ is crucial for this lethal action, establishing a minimal lethal concentration for this specific drug form.
Area of Science:
- Mycology
- Pharmaceutical Chemistry
- Antifungal Research
Background:
- Miconazole (MCZ) exhibits direct cell-damaging effects on Candida albicans.
- The pKa of miconazole's imidazole group is approximately 6.5, influencing its protonation state.
- Previous research suggested the non-protonated form (MCZ degrees) is essential for MCZ's lethal action.
Purpose of the Study:
- To further investigate the role of the non-protonated form of miconazole (MCZ degrees) in its direct lethal action against Candida albicans.
- To determine if MCZ degrees is the primary driver of cell damage, independent of pH and total drug concentration.
Main Methods:
- Testing the lethal action of miconazole against logarithmic phase Candida albicans yeasts.
- Analyzing the effect of varying pH levels on miconazole's efficacy.
- Quantifying the minimal lethal concentration of the non-protonated miconazole form (MCZ degrees).
Main Results:
- A minimal lethal concentration of 5 x 10(-6) M for MCZ degrees was established.
- This minimal lethal concentration of MCZ degrees was found to be relatively independent of pH.
- The lethal action was also found to be independent of the total miconazole concentration and the ratio of protonated (MCZH+) to non-protonated (MCZ degrees) forms.
Conclusions:
- The non-protonated form of miconazole (MCZ degrees) is directly responsible for the lethal cell damage in Candida albicans.
- A specific concentration of MCZ degrees is sufficient to kill yeast cells, irrespective of environmental pH or the overall drug concentration.
- This finding clarifies the mechanism of miconazole's fungicidal activity.