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Antimicrobial Agents and Chemotherapy, Aug 1995, 1696-1699, Vol 39, No. 8
Copyright © 1995 by the American Society for Microbiology. All rights reserved.

Fluconazole resistance due to energy-dependent drug efflux in Candida glabrata

T Parkinson, DJ Falconer and CA Hitchcock
Department of Discovery Biology, Pfizer Central Research, Sandwich, Kent, United Kingdom.

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.


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