Fluconazole resistance due to energy-dependent drug efflux in Candida glabrata.
We report on the mechanism of fluconazole resistance in Candida glabrata from a case of infection in which pre- and posttreatment isolates were available for comparison. The resistant, posttreatment isolate was cross-resistant to ketoconazole and itraconazole, in common with other azole-resistant yeasts. Resistance was due to reduced levels of accumulation of [3H]fluconazole rather than to changes at the level of ergosterol biosynthesis. Studies with metabolic or respiratory inhibitors showed that this phenomenon was a consequence of energy-dependent drug efflux, as opposed to a barrier to influx. Since energy-dependent efflux is a characteristic of multidrug resistance in bacteria, yeasts, and mammalian cells, we investigated the possibility that fluconazole resistance is mediated by a multidrug resistance-type mechanism. Benomyl, a substrate for the Candida albicans multidrug resistance protein, showed competition with fluconazole for efflux from resistance C. glabrata isolates, consistent with a common efflux mechanism for these compounds. By contrast, other standard substrates or inhibitors of multidrug resistance proteins had no effect on fluconazole efflux. In conclusion, we have identified energy-dependent efflux of fluconazole, possibly via a multidrug resistance-type transporter, as the mechanism of resistance to fluconazole in C. glabrata.
D000890:Anti-Infective Agents / Q000378:metabolism / Q000494:pharmacology*; D000963:Antimetabolites / Q000494:pharmacology; D002175:Candida / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D018432:Drug Resistance, Multiple; D004734:Energy Metabolism / Q000187:drug effects; D015725:Fluconazole / Q000378:metabolism / Q000494:pharmacology*; D024841:Fluoroquinolones; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism
D000890:Anti-Infective Agents; D000963:Antimetabolites; D024841:Fluoroquinolones; D005656:Fungal Proteins; D015725:Fluconazole