Synthetic organotellurium compounds sensitize drug resistant Candida albicans clinical isolates to fluconazole [PublishAheadOfPrint]

Invasive Candida albicans infections are a serious health threat for immunocompromised individuals. Fluconazole is most commonly used to treat these infections, but resistance due to the overexpression of multidrug efflux pumps is of grave concern. This study evaluated the ability of five synthetic organotellurium compounds to reverse fluconazole resistance of C. albicans clinical isolates. Compounds 1-4, at < 10 μg/ml, ameliorated fluconazole resistance of Saccharomyces cerevisiae strains overexpressing the major C. albicans multidrug efflux pumps Cdr1p and Mdr1p, whereas compound 5 only sensitized Mdr1p overexpressing strains to fluconazole. Compounds 1-4 also inhibited efflux of the fluorescent substrate rhodamine 6G and the ATPase activity of Cdr1p, whereas all five compounds 1-5 inhibited Nile red efflux by Mdr1p. Interestingly, all five compounds demonstrated synergy with fluconazole against efflux pump overexpressing fluconazole resistant C. albicans clinical isolates; isolate 95-142 overexpressing CDR1 and CDR2, isolate 96-25 overexpressing MDR1 and ERG11 and isolate 12-99 overexpressing CDR1, CDR2, MDR1 and ERG11. Overall, organotellurium compounds 1 and 2 were the most promising fluconazole-chemosensitizers of fluconazole resistant C. albicans isolates. Our data suggest that these novel organotellurium compounds inhibit pump efflux by two very important and distinct families of fungal multidrug efflux pumps, the ATP-binding cassette (ABC) transporter Cdr1p and the Major Facilitator Superfamily (MFS) transporter Mdr1p.

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