title: Pivotal role for a tail subunit of the RNA polymerase II mediator complex CgMed2 in azole tolerance and adherence in Candida glabrata.
abstract: Antifungal therapy failure can be associated with increased resistance to the employed antifungal agents. Candida glabrata, the second most common cause of invasive candidiasis, is intrinsically less susceptible to the azole class of antifungals and accounts for 15% of all Candida bloodstream infections. Here, we show that C. glabrata MED2 (CgMED2), which codes for a tail subunit of the RNA polymerase II Mediator complex, is required for resistance to azole antifungal drugs in C. glabrata. An inability to transcriptionally activate genes encoding a zinc finger transcriptional factor, CgPdr1, and multidrug efflux pump, CgCdr1, primarily contributes to the elevated susceptibility of the Cgmed2Δ mutant toward azole antifungals. We also report for the first time that the Cgmed2Δ mutant exhibits sensitivity to caspofungin, a constitutively activated protein kinase C-mediated cell wall integrity pathway, and elevated adherence to epithelial cells. The increased adherence of the Cgmed2Δ mutant was attributed to the elevated expression of the EPA1 and EPA7 genes. Further, our data demonstrate that CgMED2 is required for intracellular proliferation in human macrophages and modulates survival in a murine model of disseminated candidiasis. Lastly, we show an essential requirement for CgMed2, along with the Mediator middle subunit CgNut1 and the Mediator cyclin-dependent kinase/cyclin subunit CgSrb8, for the high-level fluconazole resistance conferred by the hyperactive allele of CgPdr1. Together, our findings underscore a pivotal role for CgMed2 in basal tolerance and acquired resistance to azole antifungals.
authors: Laboratory of Fungal Pathogenesis, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India.
authors: Sapan
authors: S
authors: Borah
authors: Laboratory of Fungal Pathogenesis, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India.
authors: Raju
authors: R
authors: Shivarathri
authors: Laboratory of Fungal Pathogenesis, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India.
authors: Vivek Kumar
authors: VK
authors: Srivastava
authors: Institute of Microbiology, University Hospital Lausanne and University Hospital Center, Lausanne, Switzerland.
authors: Sélène
authors: S
authors: Ferrari
authors: Institute of Microbiology, University Hospital Lausanne and University Hospital Center, Lausanne, Switzerland.
authors: Dominique
authors: D
authors: Sanglard
authors: Laboratory of Fungal Pathogenesis, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India rkaur@cdfd.org.in.
authors: Rupinder
authors: R
authors: Kaur
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D001393:Azoles / Q000494:pharmacology*; D041221:Candida glabrata / Q000187:drug effects* / Q000378:metabolism*; D005656:Fungal Proteins / Q000378:metabolism*; D012319:RNA Polymerase II / Q000378:metabolism*
chemical_list: D000935:Antifungal Agents; D001393:Azoles; D005656:Fungal Proteins; D012319:RNA Polymerase II