Multidrug Resistance Transcriptional Regulatory Networks in Candida

Abstract

Candida species are an important cause of both mucosal and invasive opportunistic infections among immuno-compromised patient populations, such as cancer patients receiving cytotoxic chemotherapy, solid-organ and bone marrow transplant patients receiving immunosuppressant therapy, and patients infected with human immunodeficiency virus (HIV) and suffering from AIDS. Moreover, recent reports have highlighted a paradoxical OPC infection rate of 30% in HIV-infected individuals who have shown improvements in CD4+ counts and have been classified as ''immune reconstituted''. This chapter focuses on the transcriptional regulation of azole antifungal resistance as well as transcriptional regulators that influence azole susceptibility in Candida species. Much of our understanding of azole antifungal resistance in Candida species has been greatly facilitated by the study of the pleiotropic drug resistance phenotype in Saccharomyces cerevisiae, which is largely driven by ATP-binding cassette (ABC) transporters such as Pdr5p. In a study to generate a more global assessment of Ndt80p, it was found that Ndt80p was bound to the promoters of many genes previously identified as being associated with azole resistance, including the ABC transporter genes CDR1, CDR2, and CDR4; the MFS transporter genes MDR1, FLU1, NAG3, and NAG4; the flippase genes RTA2 and RTA3; and other azole resistance-associated genes, PDR16, ERG3, and ERG11.