A new Aspergillus fumigatus resistance mechanism conferring in vitro cross-resistance to azole antifungals involves a combination of cyp51A alterations.
Publication year
2007Source
Antimicrobial Agents and Chemotherapy, 51, 6, (2007), pp. 1897-904ISSN
Publication type
Article / Letter to editor
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Organization
Medical Microbiology
Journal title
Antimicrobial Agents and Chemotherapy
Volume
vol. 51
Issue
iss. 6
Page start
p. 1897
Page end
p. 904
Subject
N4i 2: Invasive mycoses and compromised host; N4i 3: Poverty-related infectious diseases; NCMLS 1: Immunity, infection and tissue repair; NCMLS 1: Infection and autoimmunity; UMCN 4.1: Microbial pathogenesis and host defenseAbstract
Fourteen Aspergillus fumigatus clinical isolates that exhibited a pattern of reduced susceptibility to triazole drugs were analyzed. The sequences of the cyp51A gene from all isolates showed the presence of a point mutation at t364a, which led to the substitution of leucine 98 for histidine (L98H), together with the presence of two copies of a 34-bp sequence in tandem in the promoter of the cyp51A gene. Quantitative expression analysis (real-time PCR) showed up to an eightfold increase in the level of expression of the cyp51A gene compared to that by the susceptible strain. Three PCR fragments of one azole-resistant strain (strain CM2627) that included the promoter with the tandem repeat and part of cyp51A with the t364a mutation or PCR fragments with only one of the modifications were used to replace the cyp51A gene of an azole drug-susceptible A. fumigatus wild-type strain (strain CM237). Only transformants which had incorporated the tandem repeat in the promoter of the cyp51A gene and the L98H amino acid substitution exhibited similarly reduced patterns of susceptibility to all triazole agents and similarly increased levels of cyp51A expression, confirming that the combination of both alterations was responsible for the azole-resistant phenotype.
This item appears in the following Collection(s)
- Academic publications [238441]
- Electronic publications [122543]
- Faculty of Medical Sciences [90373]
- Open Access publications [97534]
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