Quinidine drug resistance transporter knockout Candida cells modulate glucose transporter expression and accumulate metabolites leading to enhanced azole drug resistance

Abstract

ATP-binding cassette (ABC) and Major Facilitator Superfamily (MFS) transporters have been known to play an important role in the development of multidrug resistance (MDR) in various fungal species. While the importance of ABC transporters in MDR development is widely understood, MFS exporters have gotten little attention. The role of QDR (quinidine drug resistance) transporters (CaQDR1, CaQDR2, and CaQDR3), a subfamily of MFS, in conferring pathogenicity and virulence to Candida albicans is highlighted in this study. The transcriptome analysis of QDR knockout (QDRKO) strains versus wild-type (WT) strains of C. albicans reveals differential expression of some important virulence-associated gene categories. These include chitin and β-glucan synthases, mannosyl transferases, vacuolar, ion transporters, acid phosphatase, and different sugar transporter (HGT8 and HGT9) encoding genes. Although some of the related phenotypic assays could not show any considerable differences in the growth of knockout strains under relevant stresses, however, we discovered elevated expression levels of different HGT genes in QDRKO strains, particularly under glucose limiting conditions as evidenced by the higher intracellular glucose accumulation levels. All the strains (QDRKOs and WT) followed a similar pattern in the accumulation of metabolite glycerol. Interestingly, QDRKO strains exhibit an enhanced azole drug resistance than the parental Candida strain, particularly at a low glucose concentration of the culture media. Our findings imply that deleting QDR genes (individually or collectively) alters cellular pathways, particularly those associated with glucose and glycerol accumulation. This possibly provides the cells with a mechanism to overcome stress and partially maintain the cellular pathogenicity/virulence in the absence of QDR MFS transporters.