Effect of trifluoperazine on growth, morphogenesis and pathogenicity ofCandida albicans

The calmodulin inhibitors trifluoperazine (TFP), chlorpromazine (CPZ) and R24571 inhibited the yeast-to-mycelial transition of Candida albicans in vitro. This dimorphic switch is thought to potentiate the invasion of host tissues in superficial and systemic candidosis. Growth of six strains of C. albicans and a range of other pathogenic and saprophytic fungi was inhibited by TFP in vitro with an MIC (minimum inhibitory concentration) of <31 µg ml−1 (65 µm) indicating that this compound is a general inhibitor of fungal growth. Between 20 and 60 µm TFP inhibited dimorphism markedly without completely inhibiting growth in the yeast form. This suggests that calmodulin is important in the regulation of yeast-hyphal morphogenesis and that TFP antagonizes this process thereby suppressing the yeast-to-hypha conversion. The potential of TFP as a therapeutic agent was investigated further in superficial and systemic animal models. TFP was used topically against vaginal candidosis in rats, but no significant protective antifungal effect was observed. Also, when administered orally and subcutaneously against systemic C. albicans infections in mice the ED50 was determined to be >25 mg kg−1 dose-1, too large to be considered of therapeutic value. This is in contrast to previous reports describing protective effects of TFP against candidiasis. Therefore, although TFP can inhibit growth and dimorphism of C. albicans in vitro, we conclude that this calmodulin antagonist is unsuitable as a chemotherapeutic agent.