Continuous deployment of antifungals in treating infections caused by dimorphic opportunistic pathogen Candida albicans has led to the emergence of drug resistance resulting in cross-resistance to many unrelated drugs, a phenomenon termed multidrug resistance (MDR). Despite the current understanding of major factors which contribute to MDR mechanisms, there are many lines of evidence suggesting that it is a complex interplay of multiple factors which may be contributed by still unknown mechanisms. Coincidentally with the increased usage of antifungal drugs, the number of reports for antifungal drug resistance has also increased which further highlights the need for understanding novel molecular mechanisms which can be explored to combat MDR, namely, ROS, iron, hypoxia, lipids, morphogenesis, and transcriptional and signaling networks. Considering the worrying evolution of MDR and significance of C. albicans being the most prevalent human fungal pathogen, this review summarizes these new regulatory mechanisms which could be exploited to prevent MDR development in C. albicans as established from recent studies. 1. Introduction In the last decades, the incidence of fungal infections has increased dramatically due to the rise in the number of immunocompromised patients. The most prevalent fungal pathogen of humans is Candida albicans which ranks as the fourth most common cause of hospital acquired infectious disease and is the primary cause of systemic candidiasis, with mortality rates approaching 50% [1]. The dimorphic opportunistic pathogen, C. albicans, is normally a commensal organism in humans, but when the host is unable to mount an adequate immune response, as in AIDS, organ transplant, diabetes, or in cancer patients, it results in mucosal, cutaneous, or invasive mycoses [2, 3]. Prolonged usage of antifungals in treating infections caused by C. albicans has led to the emergence of azole resistance. This acquired azole resistance in clinical isolates of C. albicans mostly results in cross-resistance to many unrelated drugs, a phenomenon termed multidrug resistance (MDR) [4–6]. MDR is a serious complication during treatment of opportunistic fungal infections which poses grave concern given the limited number of clinically useful antifungal drugs available [7, 8]. Fungal species have evolved a multitude of mechanisms to survive exposure to antifungal drugs and some of them include an overexpression or mutations in ERG11, encoding the target enzyme of azoles lanosterol 14α-demethylase [4, 5, 9, 10], an over expression of the drug efflux pumps encoding
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