We investigated the antifungal effects of sesamol (Ses), a natural phenolic compound, and exemplified that it could be mediated through disruption of calcineurin signaling pathway in C. albicans, a human fungal pathogen. The repertoire of antifungal activity not only was limited to C. albicans and its six clinical isolates tested but also was against non-albicans species of Candida. Interestingly, the antifungal effect of Ses affects neither the MDR efflux transporter activity nor passive diffusion of drug. We found that C. albicans treated with Ses copies the phenotype displayed by cells having defect in calcineurin signaling leading to sensitivity against alkaline pH, ionic, membrane, salinity, endoplasmic reticulum, and serum stresses but remained resistant to thermal stress. Furthermore, the ergosterol levels were significantly decreased by 63% confirming membrane perturbations in response to Ses as also visualized through transmission electron micrographs. Despite the fact that Ses treatment mimics the phenotype of compromised calcineurin signaling, it was independent of cell wall integrity pathway as revealed by spot assays and the scanning electron micrographs. Taken together, the data procured from this study clearly ascertains that Ses is an effectual antifungal agent that could be competently employed in treating Candida infections. 1. Introduction Candida albicans, an opportunistic human fungal pathogen, is the most common cause of the invasive fungal diseases [1]. It resides normally within the host body but during the immunosuppressed or immunocompromised conditions like AIDS, cancer, and organ transplant; it can cause several diseases such as oral thrush, vulvovaginitis, esophagitis, and cutaneous infections. It is also among the most common causative agents for nosocomial infections in patients who have undergone surgery or organ transplantation, have diabetes, and take excessive antibiotics and are neutropenic [2, 3]. Some of the most common isolates from candidiasis and candidemia are C. albicans, Candida glabrata, Candida krusei, Candida tropicalis, and Candida parapsilosis [4]. Among all Candida species C. albicans is the most prominent causative agent of the diseases [5]. Due to daily augmentation in cases of the patients suffering from the diseases caused by Candida species, it has become unavoidable to find the cure for this evader. Present treatment regime includes several classes of antifungal which are in use to treat the infection caused by the fungal pathogens. For instance azoles, polyenes and allylamines target ergosterol
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