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Increased expression and hotspot mutations of the multidrug efflux transporter, CDR1 in azole-resistant Candida albicans isolates from vaginitis patients

Looi, Chung Yeng and D'Silva, Emily Christine and Seow, Heng Fong and Rosli, Rozita and Ng, Kee Peng and Chong, Pei Pei (2005) Increased expression and hotspot mutations of the multidrug efflux transporter, CDR1 in azole-resistant Candida albicans isolates from vaginitis patients. FEMS Microbiology Letters, 249 (2). pp. 283-289. ISSN 0378-1097

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Abstract

The aims of our research were to investigate the gene expression of the multidrug efflux transporter, CDR1 and the major drug facilitator superfamily transporter, MDR1 gene in azole drug-resistant Candida albicans and Candida glabrata clinical isolates recovered from vaginitis patients; and to identify hotspot mutations that may be present in the C. albicans CaCDR1 gene that could be associated with drug-resistance. The relative expression of the CDR1 and MDR1 transcripts in ketoconazole and clotrimazole-resistant isolates and drug-susceptible ATCC strains were determined by semi-quantitative reverse transcription-polymerase chain reaction. Expression of CaCDR1 transcript was upregulated to varying extents in all three azole-resistant C. albicans isolates studied (1.6-, 3.7- and 3.9-fold) and all three C. glabrata isolates tested (at 1.9-, 2.3- and 2.7-fold). The overexpression level of CaCDR1 in the isolates correlated with the degree of resistance as reflected by the minimum inhibitory concentration (MIC) of the drugs. The messenger RNA for another efflux pump, MDR1, was also overexpressed in one of the azole-resistant C. albicans isolates that overexpressed CDR1. This finding suggests that drug-resistance may involve synergy between energy-dependent drug efflux pumps CDR1p and MDR1p in some but not all isolates. Interestingly, DNA sequence analysis of the promoter region of the CaCDR1 gene revealed several point mutations in the resistant clinical isolates compared to the susceptible isolates at 39, 49 and 151 nucleotides upstream from the ATG start codon. This finding provides new information on point mutations in the promoter region which may be responsible for the overexpression of CDR1 in drug-resistant isolates.

Item Type: Article
Uncontrolled Keywords: ResPubID19018; Candida albicans, Candida glabrata, CDR1, MDR1, mutation hotspots, Azole antifungals
Subjects: FOR Classification > 1199 Other Medical and Health Sciences
Faculty/School/Research Centre/Department > School of Biomedical and Health Sciences
Depositing User: VUIR
Date Deposited: 01 Feb 2012 05:14
Last Modified: 22 Jan 2015 22:05
URI: http://vuir.vu.edu.au/id/eprint/2807
DOI: 10.1016/j.femsle.2005.06.036
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Citations in Scopus: 8 - View on Scopus

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