Transcriptional analyses of antifungal drug resistance in Candida albicans

Oral infections with the pathogenic yeast Candida albicans are one of the m ost frequent and earliest opportunistic infections in human immunodeficienc y virus-infected patients. The widespread use of azole antifungal drugs has led to the development of drug-resistant isolates. Several molecular mecha nisms that contribute to drug resistance have been identified, including in creased mRNA levels for two types of efflux pump genes: the ATP binding cas sette transporter CDRs (CDR1 and CDR2) and the major facilitator MDR1. Usin g Northern blot analyses, the expression patterns of these genes have been determined during logarithmic and stationary phases of cell growth and duri ng growth in different carbon sources in a set of matched susceptible and f luconazole-resistant isolates that have been characterized previously. MDR1 , CDR1, and CDR2 are expressed early during logarithmic growth, CDR4 is exp ressed late during logarithmic growth, and CDR1 is preferentially expressed in stationary-phase cells. There Is a small decrease in expression of thes e genes when the cells are grown in carbon sources other than glucose. Whil e increased mRNA levels of efflux pump genes are commonly associated with a zole resistance, the causes of increased mRNA levels have not yet been reso lved. Southern blot analysis demonstrates that the increased mRNA levels in these isolates are not the result of gene amplification. Nuclear run-on as says show that MDR1 and CDR mRNAs are transcriptionally overexpressed in th e resistant isolate, suggesting that the antifungal drug resistance in this series is associated with the promoter and trans-acting factors of the CDR 1, CDR2, and MDR1 genes.