Drug sensitivity and resistance mechanism in Aspergillus section Nigri strains from Japan [PublishAheadOfPrint]

Aspergillus niger and its related species, known as Aspergillus section Nigri, are ubiquitously distributed across the globe and are often isolated from clinical specimens. In Japan, Aspergillus section Nigri is the second-most often isolated from clinical specimens following A. fumigatus. We determined the species of Aspergillus section Nigri isolated in Japan by DNA sequencing of partial β-tubulin genes and investigated drug susceptibility by CLSI M38-A2 method. The collection contained 20 A. niger, 59 A. welwitschiae, and 39 A. tubingensis strains. Drug susceptibility testing revealed 30-55% of A. niger, 6.8-18.6% of A. welwitschiae, and 79.5-89.7% of A. tubingensis to be less susceptible (so-called resistant) to itraconazole (ITC) and/or voriconazole (VRC) according to the epidemiologic cutoff values (ECVs) proposed for A. niger previously. Minimum inhibitory concentrations distributions of ITC or VRC showed no remarkable differences between clinical and environmental isolates. When the cyp51A sequences were compared between susceptible and resistant strains, 18 amino acid mutations were specific for resistant isolates of A. niger and A. tubingensis, however none of them were confirmed to be associated with azole resistance. Three non-related A. welwitschiae isolates possessed a partial deletion in cyp51A, likely attributable to being more susceptible to azoles when compared to other isolates. 1 of 5 ITC-resistant A. tubingensis isolates showed higher expression level of cyp51A than those of susceptible strains. Our results show that cyp51A point mutations may have no association with azole resistance but in some cases the over-expression of cyp51A might lead the azole-resistance in these species.

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