Analyses of fluconazole uptake in clinical isolates of , with wide ranging drug resistance profiles, has revealed interesting differences within the species as well as major distinctions from other yeast species. We previously proposed that prevention of drug uptake is a potential mechanism of drug resistance and our data provide further support for this.

We developed an assay using radio-labeled fluconazole to measure intracellular azole accumulation in fungal cells. The assay is performed under glucose-replete conditions to inhibit ATP-dependent efflux. A comparative study measuring fluconazole uptake in 63 isolates as well as a panel of other species such as , , and revealed striking phenotypes that we have not seen in other fungal species.

There is a strong correlation between fluconazole resistance and reduced drug uptake in . Fluconazole-resistant isolates had reduced levels of intracellular fluconazole accumulation compared to susceptible isolates. Drug-resistant isolates had the lowest drug accumulation of any of the yeast species tested. Fluconazole-susceptible isolates had dramatically increased fluconazole accumulation compared to the resistant isolates as well as when compared to other yeast species.

Of the 63 isolates, 28 of 32 (∼88%) resistant isolates had extremely low fluconazole uptake, whereas 15 of 18 (∼83%) susceptible isolates had high fluconazole uptake. This association between reduced drug uptake and resistance could be a -distinctive mechanism of drug resistance.

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