Differences in interactions between azole drugs related to modifications in the 14-α sterol demethylase gene (cyp51A) of Aspergillus fumigatus (original) (raw)
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Antimicrobial Agents and Chemotherapy, 2004
Five clinical isolates of Aspergillus fumigatus that exhibited similar patterns of reduced susceptibility to itraconazole and other triazole drugs were analyzed. Sequence analysis of genes (cyp51A and cyp51B) encoding the 14␣-sterol demethylases revealed that all five strains harbored mutations in cyp51A resulting in the replacement of methionine at residue 220 by valine, lysine, or threonine. When the mutated cyp51A genes were introduced into an A. fumigatus wild-type strain, the transformants exhibited reduced susceptibility to all triazole agents, confirming that the mutations were responsible for the resistance phenotype.
Multi-azole resistance in Aspergillus fumigatus
International Journal of Antimicrobial Agents, 2006
Azole resistance in Aspergillus spp. is unusual. We report a patient who received long-term treatment with itraconazole and voriconazole for bilateral chronic cavitary aspergillosis with aspergillomas whose isolates of Aspergillus fumigatus developed simultaneous resistance to itraconazole and voriconazole. A novel mutation (G138C) in the target gene (cyp51A) encoding 14␣-demethylase was detected. The patient had some response to intravenous caspofungin, which he received six times weekly, without the development of resistance over 9 months.
Epidemiological Cutoffs and Cross-Resistance to Azole Drugs in Aspergillus fumigatus
Antimicrobial Agents and Chemotherapy, 2008
Antifungal susceptibility testing of molds has been standardized in Europe and in the United States. Aspergillus fumigatus strains with resistance to azole drugs have recently been detected and the underlying molecular mechanisms of resistance characterized. Three hundred and ninety-three isolates, including 32 itraconazole-resistant strains, were used to define wild-type populations, epidemiological cutoffs, and cross-resistance between azole drugs. The epidemiological cutoff for itraconazole, voriconazole, and ravuconazole for the wild-type populations of A. fumigatus was ≤1 mg/liter. For posaconazole, the epidemiological cutoff was ≤0.25 mg/liter. Up till now, isolates susceptible to itraconazole have not yet displayed resistance to other azole drugs. Cross-resistance between azole drugs depends on specific mutations in cyp51A. Thus, a substitution of glycine in position 54 of Cyp51A confers cross-resistance between itraconazole and posaconazole. A substitution of methionine at p...
Genes, 2020
Infections caused by Aspergillus species are being increasingly reported. Aspergillus flavus is the second most common species within this genus causing invasive infections in humans, and isolates showing azole resistance have been recently described. A. flavus has three cyp51-related genes (cyp51A, cyp51B, and cyp51C) encoding 14-α sterol demethylase-like enzymes which are the target of azole drugs. In order to study triazole drug resistance in A. flavus, three strains showing reduced azole susceptibility and 17 azole susceptible isolates were compared. The three cyp51-related genes were amplified and sequenced. A comparison of the deduced Cyp51A, Cyp51B, and Cyp51C protein sequences with other protein sequences from orthologous genes in different filamentous fungi led to a protein identity that ranged from 50% to 80%. Cyp51A and Cyp51C presented several synonymous and non-synonymous point mutations among both susceptible and non-susceptible strains. However, two amino acid mutatio...
Emerging Infectious Diseases, 2009
Azoles are the mainstay of oral therapy for aspergillosis. Azole resistance in Aspergillus has been reported infrequently. The first resistant isolate in Manchester, UK, was detected in 1999. In a clinical collection of 519 A. fumigatus isolates, the frequency of itraconazole resistance was 5%, a significant increase since 2004 (p<0.001). Of the 34 itraconazole-resistant isolates we studied, 65% were cross-resistant to voriconazole and 74% (25) were crossresistant to posaconazole. Thirteen of 14 evaluable patients in our study had prior azole exposure; 8 infections failed therapy (progressed), and 5 failed to improve (remained stable). Eighteen amino acid alterations were found in the target enzyme, Cyp51A, 4 of which were novel. A population genetic analysis of microsatellites showed the existence of resistant mutants that evolved from originally susceptible strains, different cyp51A mutations in the same strain, and microalterations in microsatellite repeat number. Azole resistance in A. fumigatus is an emerging problem and may develop during azole therapy.
Azole antifungal resistance in Aspergillus fumigatus: 2008 and 2009
Journal of Antimicrobial Chemotherapy, 2010
to itraconazole, voriconazole and posaconazole. We undertook CYP51A sequencing for most of the azole-resistant isolates. Results: Of 230 isolates, 64 (28%) were azole resistant. In 2008 and 2009, 14% and 20% of patients had resistant isolates, respectively. During this period 62 of 64 (97%) were itraconazole resistant, 2 of 64 (3%) were only voriconazole resistant and 78% of cases were multi-azole resistant. Forty-three percent of isolates did not carry a cyp51A mutation (previously the most common azole resistance mechanism), indicating that other mechanisms must be responsible and are increasing in frequency. Conclusions: Azole resistance is evolving and growing in frequency. Established and novel mechanisms may be responsible.