Invasive fungal infections kill over 1.5 million people a year worldwide, and this number is on the rise due to increasing numbers of people living with compromised immunity, including the elderly, premature infants, transplant recipients, and cancer patients. The Candida species alone is responsible for approx. 400,000 bloodstream infections annually worldwide, with an associated mortality rate of 46-75%. The Chauhan laboratory is interested in understanding the fundamental question that allow Candida species to switch from a relatively benign commensal organism to a deadly pathogen. We study the two most common fungal pathogens of the Candida genus: C. albicans and C. glabrata. Current efforts are focused on:
- Our lab is interested in understanding the epigenetic mechanisms that affect fungal virulence. Specifically, we are interested in the role of post-translational modification of proteins via lysine acetylation. Lysine acetylation is a well-established major mechanism of regulating protein function, and lysine acetylases have been shown to play important roles in many cellular processes. Protein acetylation status is affected in several types of cancer, as well as neurodegenerative diseases. For these reasons, lysine deacetylases (KDACs) have received considerable attention as drug targets and several KDAC inhibitors are currently in development as anticancer drugs. However, the effect of these modifications on protein function and the cellular pathways affected by them are still poorly understood in albicans and other fungal pathogens. We use molecular, genetic, biochemical and immunological approaches to study function of these epigenetic modifiers. The long term goal of this research is to define the role of protein acetylation in Candida species pathogenesis, with a long-term objective of identifying new drug targets for antifungal therapies.
- A second major goal is to develop assays to screen for inhibitors of antifungal drug targets. The current paradigm for drug discovery is predicated on the idea that an optimal drug target must be essential for growth and/or viability of the pathogen. In contrast, we suggest that compounds that inhibit the virulence of fungal pathogens without necessarily affecting their growth and viability should also be considered during antifungal drug discovery. This hypothesis was recently discussed in regard to antibacterial drug discovery but has not been applied to antifungal drugs. Thus, we distinguish “virulence-essential” from “growth-essential” gene products since most proteins in the former category are not required for growth in vitro. One advantage of using targeting virulence-essential but not growth-essential fungal genes is that this is expected to reduce the selective pressure acting on the pathogen that drives the emergence of drug resistant mutants. We are currently utilizing a new reporter-based assay developed in our lab for identifying small molecules that inhibit the expression of a reporter gene dependent on the functional two-component system.
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Khandelwal NK, Chauhan N, Sarkar P, Esquivel BD, Coccetti P, Singh A, Coste AT, Gupta M, Sanglard D, White TC, Chauvel M, d’Enfert C, Chattopadhyay A, Gaur NA, Mondal AK, Prasad R (2018) Azole resistance in a Candida albicans mutant lacking the ABC transporter CDR6/ROA1 depends on TOR signaling. J Biol Chem 293: 412-432. PMI: 29158264
Jenull S, Tscherner M, Gulati M, Nobile CJ, Chauhan N, Kuchler K (2017) The Candida albicans HIR histone chaperone regulates the yeast-to-hyphae transition by controlling the sensitivity to morphogenesis signals. Sci Rep 7: 8308. PMI: 28814742
Kuchler K, Jenull S, Shivarathri R, Chauhan N (2016) Fungal KATs/KDACs: A New Highway to Better Antifungal Drugs? PLoS Pathog 12: e1005938. PMI: 27832212
Tscherner M, Zwolanek F, Jenull S, Sedlazeck FJ, Petryshyn A, Frohner IE, Mavrianos J, Chauhan N, von Haeseler A, Kuchler K (2015) The Candida albicans Histone Acetyltransferase Hat1 Regulates Stress Resistance and Virulence via Distinct Chromatin Assembly Pathways. PLoS Pathog 11: e1005218. PMI: 26473952
Shor E, Chauhan N (2015) A case for two-component signaling systems as antifungal drug targets. PLoS Pathog 11: e1004632. PMI: 25723524
Mavrianos J, Desai C, Chauhan N (2014) Two-component histidine phosphotransfer protein Ypd1 is not essential for viability in Candida albicans. Eukaryot Cell. PMI: 24489039