Aspergillus fumigatus cyp51A polymorphisms, an insight on their significance. [PublishAheadOfPrint]

Triazole antifungal compounds are the first treatment choice for invasive aspergillosis. However, in the last decade Aspergillus fumigatus azole resistance has increased notoriously. The main resistance mechanisms are well-defined and mostly related to point mutations of the azole target, 14-α sterol demethylase (cyp51A), with or without tandem repeat integrations in the cyp51A promoter. Furthermore, different combinations of five Cyp51A mutations (F46Y, M172V, N248T, D255E and E427K) have been reported worldwide in around 10% of the total A. fumigatus isolated. The azole susceptibility profile of these strains shows elevated azole minimum inhibitory concentrations, although based on azole susceptibility breakpoints these strains are not considered as azole resistant. The purpose of the study was to determine whether these cyp51A polymorphisms (SNPs) are responsible for the azole susceptibility profile and whether they are reflected in a poorer azole treatment response in vivo that could compromise patient treatment and outcome. A cyp51A deleted mutant was generated, becoming fully susceptible to all azoles tested. Also, three gene constructions with different combinations of cyp51A-SNPs were generated and re-introduced in an azole susceptible wild-type (WT) strain (akuB^KU80). The alternative model host Galleria mellonella was used to compare virulence and voriconazole response of infected larvae with A. fumigatus cyp51A-WT or cyp51A-SNP strains. All strains were pathogenic in G. mellonella although they did not respond similarly to voriconazole therapeutic doses. Finally, these strains were full genome sequenced and analyzed in comparison with A. fumigatus-WT strains, revealing that they belong to different strain clusters or lineages.

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