Hijacking the Candida albicans Multidrug Resistant Transporter MDR1 to Potentiate Antifungal Activity
Fungal invasive infections of humans are now called "hidden killers". The rising costs of treatment are associated with inappropriate therapy, defined as delayed intervention, inadequate dosage, or administration of an antifungal to which an isolate was considered drug resistant. Treatment failure is commonly due to resistance to triazoles in multi-drug resistant (MDR) fungi. For life-threatening fungal infections, such as those caused by Candida albicans, overexpression of MDR1, which encodes an MDR efflux pump of the major facilitator superfamily, often confers resistance to chemically unrelated substances, including the most commonly used azole antifungals. Further, gain-of-function mutations in the fungal zinc-cluster transcription factor MRR1 are responsible for MDR1 overexpression. I used standardized assays with C. albicans and A. fumigatus to determine berberine susceptibilities. Interestingly, I found that MDR resistant isolates of C. albicans were hypersusceptible to berberine. Strains lacking MDR1 or its transcriptional regulator MRR1 were not hypersusceptible to berberine. I demonstrated that MDR isolates accumulated berberine intracellularly. Microarray comparisons showed an extensive upregulation of MDR1 as well as other importers of the drug: H+ antiporter DHA1 family of polyamine transporters in an azole resistant strain. Substrates of polyamine transporters inhibited berberine activity, and a transporter kinase mutant was resistant to berberine. I propose that these upregulated transporters augment berberine accumulation. A berberine derivative selectively accumulated in mitochondria. By Gene Set Enrichment Analysis (GSEA), I found mitochondrial genes were affected by berberine treatment. I then showed biochemically that berberine damages C. albicans mitochondria. This report is the first to demonstrate that overexpression of the MDR1 transporter renders the susceptibility to berberine in C. albicans. As a conclusion, I demonstrate an experimental proof of principle that MDR C. albicans isolates are hypersusceptible to berberine and that berberine accumulates intracellularly via Mdr1p and other transporters. I recommend identifying berberine derivatives that are even more active in treating MDR fungal infections.
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