Sneh Lata Panwar

Candida albicans is a natural component of the human flora that can cause life-threatening infections in immunosuppressed patients. Treatment of fungal infections is a challenge due to the limited repertoire of available antifungals. Additionally, both the planktonic as well as biofilm modes of growth of C. albicans develop resistance to existing azole antifungals due to the upregulation of drug efflux pumps, posing a challenge in treating Candida infections. This necessitates the need to identify additional cellular targets for antifungal therapy. In this context, our lab focuses on dissecting various cellular processes that are regulated by the mitochondria and the seven-transmembrane receptor family of proteins (Rta2, Rta3 and Rta4), in an attempt to identify features that are unique to C. albicans.  We propose that targeting the mitochondria and the Rta family of proteins will increase the antifungal target space and will provide powerful strategy to treat fungal infections. We have shown that mitochondria are required for modulating drug resistance, lipid homeostasis, Hog1-mediated oxidative stress pathway, iron homeostasis and ergosterol levels in C. albicans.

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The Rta1-like family in S. cerevisiae was initially named LTE, for lipid-translocating exporter, based on the finding that Rsb1 is involved in the release of sphingoid bases. In C. albicans Rta1 family of proteins are unique to fungal kingdom and can be considered as potential therapeutic targets. Functional analysis of the Rta1 family of proteins has revealed their importance in regulating a plethora of functions such as modulating ER stress response and asymmetric distribution of phosphatidylcholine across the plasma membrane. Additionally we show that all these proteins are involved in regulating biofilm formation in C. albicans. Considering that biofilm-specific drugs do not exist in C. albicans, targeting these genes may have therapeutic implications that may contribute to the development of biofilm-specific antifungals.

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The upregulation of the drug efflux pumps, Cdr1 and Cdr2 in drug resistant C. albicans isolates is often accompanied by the simultaneous induction of a subset of genes (RTA3, IFU5 and HSP12) via the transcription factor Tac1. The significance of these co-regulated genes remains largely unexplored in C. albicans, which prompted us to ask if these proteins contribute to the development of azole resistance in C. albicans by affecting the function of Cdr1 and Cdr2. Thus, in order to investigate the relevance of Tac1 co-regulated genes, we characterized Ifu5, a WW domain-containing protein, in this pathogenic fungus. We demonstrate the role of Tac1-regulated Ifu5 in mediating normoxic and hypoxic responses in C. albicans. ifu5Δ/Δ cells display defects in cell wall physiology and hyphal morphogenesis under normoxia. Furthermore, we demonstrate that Ifu5 in alliance with the hypoxic regulator Efg1 may contribute to hypoxic adaptation in C. albicans.

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Our laboratory has also made considerable progress in providing mechanistic insights into the functions of these aforesaid cellular novel antifungal targets.; all are unique to the fungal kingdom. We are currently interested in identifying compounds that will selectively inhibit the aforesaid proteins in C. albicans, paving a way for identifying new antifungals that may also be specific to the biofilm-based infections.