Expression of the CDR1 efflux pump in clinical Candida albicans isolates is controlled by a negative regulatory element
- Membrane Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi (India)
- Special Center for Molecular Medicine, Jawaharlal Nehru University, New Delhi (India)
- University of Bonn, Bonn (Germany)
- University of Wuerzburg, Wuerzburg (Germany)
Resistance to azole antifungal drugs in clinical isolates of the human fungal pathogen Candida albicans is often caused by constitutive overexpression of the CDR1 gene, which encodes a multidrug efflux pump of the ABC transporter superfamily. To understand the relevance of a recently identified negative regulatory element (NRE) in the CDR1 promoter for the control of CDR1 expression in the clinical scenario, we investigated the effect of mutation or deletion of the NRE on CDR1 expression in two matched pairs of azole-sensitive and resistant clinical isolates of C. albicans. Expression of GFP or lacZ reporter genes from the wild type CDR1 promoter was much higher in the azole-resistant C. albicans isolates than in the azole-susceptible isolates, reflecting the known differences in CDR1 expression in these strains. Deletion or mutation of the NRE resulted in enhanced reporter gene expression in azole-sensitive strains, but did not further increase the already high CDR1 promoter activity in the azole-resistant strains. In agreement with these findings, electrophoretic mobility shift assays showed a reduced binding to the NRE of nuclear extracts from the resistant C. albicans isolates as compared with extracts from the sensitive isolates. These results demonstrate that the NRE is involved in maintaining CDR1 expression at basal levels and that this repression is overcome in azole-resistant clinical C. albicans isolates, resulting in constitutive CDR1 overexpression and concomitant drug resistance.
- OSTI ID:
- 20710822
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 332, Issue 1; Other Information: DOI: 10.1016/j.bbrc.2005.04.113; PII: S0006-291X(05)00883-1; Copyright (c) 2005 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
Similar Records
Multi-omics Signature of Candida auris, an Emerging and Multidrug-Resistant Pathogen
Zap1 is required for Candida glabrata response to fluconazole