New resistance mechanisms to azole drugs in Aspergillus fumigatus and emergence of antifungal drugs-resistant A. fumigatus atypical strains.

Abstract

Azole drug resistance in Aspergillus fumigatus is an uncommon but well-known phenomenon. The analysis of resistance mechanisms at molecular level has identified the bases for A. fumigatus azole resistance. To date, the most prevalent mechanism of azole resistance appears to be the modification of Cyp51, specifically mutations in cyp51A gene. These mutations have been associated with three different antifungal susceptibility profiles: (i) cross-resistance to itraconazole and posaconazole that has been associated with amino acid substitutions at glycine 54 (G54), (ii) elevated MICs to all azole drugs associated with amino acid substitutions at methionine M220, and (iii) cross-resistance to all azole drugs related to the presence of Cyp51A substitutions at leucine 98 for histidine (L98H) linked to a duplication in tandem of a 34 bp repeat in the cyp51A promoter region, which seem to be responsible for increased cyp51A gene expression. Another matter of concern is the increasing reports of isolation of genetic variants of A. fumigatus, originally misidentified as poorly sporulating strains of A. fumigauts, as a causative agents of invasive infection. Many of these isolates belonging to the Aspergillus section Fumigati have been found to be resistant in vitro to multiple antifungal drugs. Current data show that susceptibility profile of these variants could be predictable depending on the species. Resistance among clinical strains of filamentous fungi may become more common in the future associated with the spread of prophylaxis, pre-emptive treatments and specific therapies with antifungal agents.