Requirement for nonprotonated drug molecules in the direct lethal action of miconazole against Candida albicans

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Abstract
At ≥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 ∼ 6.5. Thus, in media of pH >6.5 most drug molecules are nonprotonated (MCZ∘). Conversely, at pH < 6.5 the majority are protonated and carry a positive charge (MCZH+). Our earlier work suggesting that MCZ∘ is required for direct lethal action was tested further. In support of such a requirement, we established a minimal lethal concentration of MCZ∘ (i.e. 5×10−6 M) that was relatively independent of pH, MCZ concentration, and MCZ∘∶MCZH+ ratio.