title: Functional characterization of Candida albicans Hos2 histone deacetylase.
abstract: Candida albicans is a mucosal commensal organism capable of causing superficial (oral and vaginal thrush) infections in immune normal hosts, but is a major pathogen causing systemic and mucosal infections in immunocompromised individuals. Azoles have been very effective anti-fungal agents and the mainstay in treating opportunistic mold and yeast infections. Azole resistant strains have emerged compromising the utility of this class of drugs. It has been shown that azole resistance can be reversed by the co-administration of a histone deacetylase (HDAC) inhibitor, suggesting that resistance is mediated by epigenetic mechanisms possibly involving Hos2, a fungal deacetylase. We report here the cloning and functional characterization of  HOS2 (High Osmolarity  Sensitive) , a gene coding for fungal histone deacetylase from  C. albicans. Inhibition studies showed that Hos2 is susceptible to pan inhibitors such as trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA), but is not inhibited by class I inhibitors such as MS-275. This  in  vitro enzymatic assay, which is amenable to high throughput could be used for screening potent fungal Hos2 inhibitors that could be a potential anti-fungal adjuvant. Purified Hos2 protein consistently deacetylated tubulins, rather than histones from TSA-treated cells. Hos2 has been reported to be a putative NAD+ dependent histone deacetylase, a feature of sirtuins. We assayed for sirtuin activation with resveratrol and purified Hos2 protein and did not find any sirtuin activity.
authors.affiliation: Drug Discovery Research, Orchid Chemicals and Pharmaceuticals Limited, Chennai, 600 119, India.
authors.forename: G
authors.initials: G
authors.lastname: Karthikeyan
authors.affiliation: Drug Discovery Research, Orchid Chemicals and Pharmaceuticals Limited, Chennai, 600 119, India ; Current address: Samrud Foundation for Health & Research, Bangalore, 560106, India.
authors.forename: Maneesh
authors.initials: M
authors.lastname: Paul-Satyaseela
authors.affiliation: Drug Discovery Research, Orchid Chemicals and Pharmaceuticals Limited, Chennai, 600 119, India.
authors.forename: Nachiappan
authors.initials: N
authors.lastname: Dhatchana Moorthy
authors.affiliation: Drug Discovery Research, Orchid Chemicals and Pharmaceuticals Limited, Chennai, 600 119, India.
authors.forename: Radha
authors.initials: R
authors.lastname: Gopalaswamy
authors.affiliation: Drug Discovery Research, Orchid Chemicals and Pharmaceuticals Limited, Chennai, 600 119, India ; Current address: AstraZeneca India Pvt. Ltd, Bengaluru, 560024, India.
authors.forename: Shridhar
authors.initials: S
authors.lastname: Narayanan