Summary auto-generated
This study identifies and characterizes CDR2, a new multidrug ABC transporter gene in Candida albicans that contributes to resistance against azole antifungal agents. Using a complementation screen in Saccharomyces cerevisiae, the authors isolated multiple C. albicans genes conferring azole resistance. CDR2 encodes a 168 kDa protein showing 84% identity to the previously known Cdr1p transporter. The protein confers resistance to azoles, other antifungals (terbinafine, amorolfine), and various metabolic inhibitors. Notably, CDR2 mRNA was absent in azole-susceptible clinical isolates but was overexpressed in azole-resistant strains, often at levels exceeding or equal to CDR1. Gene disruption experiments revealed that deletion of CDR2 alone did not increase susceptibility, but deletion of both CDR1 and CDR2 resulted in heightened sensitivity compared to CDR1 deletion alone. The findings demonstrate that CDR2 plays a significant role in mediating azole resistance in C. albicans, alongside CDR1.
Key findings
- CDR2 is a new ABC transporter gene in C. albicans that encodes a protein 84% identical to the known resistance transporter Cdr1p
- CDR2 is overexpressed in clinical azole-resistant C. albicans isolates but not expressed in azole-susceptible strains
- CDR2 confers multidrug resistance including to azoles, terbinafine, amorolfine, and various metabolic inhibitors
- The double mutant lacking both CDR1 and CDR2 shows greater susceptibility to antifungals than CDR1 deletion alone, indicating both transporters contribute to resistance
This summary was generated automatically from the article PDF and is not part of the original publication. Refer to the PDF for the authoritative text.
Abstract
Resistance to azole antifungal agents in Candida albicans can be mediated by multidrug efflux transporters. In a previous study, we identified at least two such transporters, Cdr1p and Benp, which belong to the class of ATP-binding cassette (ABC) transporters and of major facilitators, respectively. To isolate additional factors potentially responsible for resistance to azole antifungal agents in C. albicans, the hypersusceptibility of a Saccharomyces cerevisiae multidrug transporter mutant, δpdr5, to these agents was complemented with a C. albicans genomic library. Several new genes were isolated, one of which was a new ABC transporter gene called CDR2 (Candida drug resistance). The protein Cdr2p encoded by this gene exhibited 84% identity with Cdr1p and could confer resistance to azole antifungal agents, to other antifungals (terbinafine, amorolfine) and to a variety of metabolic inhibitors. The disruption of CDR2 in the C. albicans strain CAF4-2 did not render cells more susceptible to these substances. When the disruption of CDR2 was performed in the background of a mutant in which CDR1 was deleted, the resulting double δcdr1 δcdr2 mutant was more susceptible to these agents than the single δcdr1 mutant. The absence of hypersusceptibility of the single δcdr2 mutant could be explained by the absence of CDR2 mRNA in azole-susceptible C albicans strains. CDR2 was overexpressed, however, in clinical C. albicans isolates resistant to azole antifungal agents as described previously for CDR1, but to levels exceeding or equal to those reached by CDR1. Interestingly, CDR2 expression was restored in δcdr1 mutants reverting spontaneously to wild-type levels of susceptibility to azole antifungal agents. These data demonstrate that CDR2 plays an important role in mediating the resistance of C. albicans to azole antifungal agents.