The magnitude of azole resistance in Aspergillus flavus and the underlying mechanism is obscure. We evaluated the frequency of azole resistance in a collection of clinical (n=121) and environmental isolates (n=68) of A. flavus by broth microdilution method. Six (5%) clinical isolates displayed voriconazole minimum inhibitory concentration (MIC) greater than the epidemiological cut-off value. Two of these isolates with non-wild-type MIC were isolated from same patient and were genetically distinct, which was confirmed by amplified length polymorphism. Mutations associated with azole resistance were not present in the lanosterol 14-α demethylase coding genes (cyp51A, cyp51B and cyp51C). Basal and voriconazole-induced expression of cyp51A homologs and various efflux pump genes was analyzed in three each of non-wild type and wild-type isolates. All the efflux pump genes screened showed low basal expression irrespective of the azole susceptibility of the isolate. However, the non-wild type isolates demonstrated heterogeneous overexpression of many efflux pumps and the target enzyme coding genes in response to induction with voriconazole (1μg/mL). The most distinctive observation was approximately 8-9 fold voriconazole-induced overexpression of an ortholog of Candida albicans ABC multidrug efflux transporter, Cdr1 in two non-wildtype isolates as compared to the reference strain A. flavus ATCC204304 and other wild type strains. Although the dominant marker of azole resistance in A. flavus is still elusive, the current study proposes the possible role of multidrug efflux pumps, especially Cdr1B overexpression in contributing azole resistance in A. flavus.
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