PMID:12709346 Multiple resistance mechanisms among Aspergillus fumigatus mutants with high-level resistance to itraconazole.

[MPiovesana]

Curated by @MPiovesana https://canto.phi-base.org/curs/19bec1e8b7ca6406

[MPiovesana]

The authors of this paper generate itraconazole-resistant mutants derived from a wild type strain of Aspergillus fumigatus in laboratory conditions. Among the mutants generated, a few of them are found to carry point mutations in the target gene cyp51A, as shown in Table 1. Other mutants are found to overexpress novel drug efflux pumps described in the paper. For the purpose of curation in PHI-Canto, I believe the amino acid substitution genotypes can be curated, as we know the mutation associated with the resistance phenotype. I am not sure we can curate the other mutants (the ones not harbouring point mutations), as we do not know the mechanism via which overexpression of the drug efflux pumps is achieved (promoter mutation? mutation in regulatory gene?). So for now, I have curated the three point mutation alleles described in the paper.

[MPiovesana]

Uniprot ID: no problems locating the ID of cyp51A of A. fumigatus (Q4WNT5).

AC: reviewed entry :-) https://www.uniprot.org/uniprotkb/Q4WNT5/entry

[MPiovesana]

Strain: wt strain H11-20 was used for the UV-irradiation mutagenesis experiment.

[MPiovesana]

Genotype creation: three genotypes harbouring amino acid substitution allele types were created to record the three point mutations identified in cyp51A: G54E/K/R. All alleles were assigned with expression level Not assayed, as levels of cyp51A were not measured in the study (only of the drug efflux pumps).

[MPiovesana]

Genotype annotation: all three pathogen genotypes were annotated with PHIPO term resistance to itraconazole.

[MPiovesana]

Curation completed pending review.

[CuzickA]

AE alteration in archetype

G54E; Cyp51A; ASPEFU G54K; Cyp51A; ASPEFU G54R; Cyp51A; ASPEFU

No entry found in Nichola's S files STable 2

Information found in Mair et al 2016 Table 2

[CuzickA]

Will approve session once AE alteration in archetype checked. Closing ticket.

[CuzickA]

AE alteration_in _archetype checked by Nichola. Session now approved.