Mrr2 mutations and upregulation are associated with increased fluconazole resistance in Candida albicans isolates from patients with vulvovaginal candidiasis

Abstract

Candida albicans is an opportunistic fungus, which causes vulvovaginal candidiasis (VVC). The aim of this study was to evaluate Mrr2 mutation and its expression levels and Candida drug resistance 1 (Cdr1) in C. albicans associated with fluconazole (FCA) resistance. We identified 80 isolates of C. albicans from 155 vaginal secretions and performed FCA drug sensitivity tests, using M27-A3 micro-broth dilution. We extracted DNA, sequenced Mrr2, and performed reverse transcriptase-quantitative PCR polymerase chain reaction (RT-qPCR) to detect mRNA expression levels of Mrr2 and Cdr1. In total, 40 isolates were sensitive, 10 were dose-dependently sensitive, and 30 were resistant to FCA. Mrr2 mutation occurred in 56·67% isolates, which was significantly higher than that in the FCA sensitive group (26·08%, P < 0·05). The mRNA expression level of Cdr1 in the FCA resistant group was significantly higher than that in the sensitive group Cdr1 (0·42 ± 0·294 vs 0·25 ± 0·289, P < 0·05). The odds ratio of FCA-resistant occurrence in C. albicans with Mrr2 mutation and high expression levels was 47·5 times higher than C. albicans without Mrr2 mutation and low expression levels. The results may provide new insights for improving VVC treatment. SIGNIFICANCE AND IMPACT OF THE STUDY: Significance and Impact of the Study: Candida albicans is an opportunistic fungus, which causes vulvovaginal candidiasis (VVC). Fluconazole (FCA) is the most widely used drug in VVC infection. However, the widespread use of FCA has severely increased the incidence of FCA-resistant fungus. Therefore, the mechanism underlying FCA resistance in C. albicans must be elucidated urgently. This study demonstrated that high expression of Cdr1 and Mrr2 may directly be linked to C. albicans resistance to FCA, and high expression of Mrr2 may promote high expression of Cdr1 and mediate resistance of C. albicans to FCA. The results may provide new insights for improving VVC treatment.

Keywords: Candida albicans; Cdr1; Mrr2; fluconazole; vulvovaginal candidiasis.