Investigation of mutations in transcription factors of the efflux pump genes in efflux pump overexpressing fluconazole resistant/dose dependent susceptible candida albicans strains

In recent years, the number of immune compromised patients and the frequency of Candida albicans infections in these patients has been increasing. In parallel, there has been an increase in the clinical use of fluconazole, a well tolareted antifungal agent with moderate side effects, along with a rise in fluconazole resistance. The most frequent mechanism of fluconazoe resistance in C. albicans involves overexpression of CDR1, CDR2 and MDR1 genes and transportation of the drug out of the cell via Cdr1, Cdr2 ve Mdr1 efflux pumps encoded by these genes. It has been shown that, the overexpression of these efflux pump genes was caused by gain of function mutations in TAC1 and MRR1 genes which encode the transcription factors Tac1p and Mrr1p. This study was aimed to analyze TAC1 and MRR1 genes of 17 C. albicans strains which consist of seven fluconazole susceptible, four trailing effect showing susceptible and six fluconazole resistant isolates for gain of function mutations with polymerase chain reaction and sequence analysis. In conclusion, two of the fluconazole resistant isolates which overexpress Cdr1 and Cdr2 pumps, revealed R673Q and A736V mutations which had been reported to cause overexpression of TAC1 gene. Also a P683H point mutation, which was known to cause MRR1 overexpression was detected in a fluconazole resistant strain that overexpressed the Mdr1 pump. As a result, it can be concluded that, gain of function mutations in the transcription factors of the efflux pump genes play an important role in resistance to fluconazole in our C. albicans strains. Key words: Candida albicans, fluconazole resistance, efflux pumps, transcription factors, TAC1, MRR1, cdr1, cdr2, mdr1