Increased resistance to 14α-demethylase inhibitors (DMIs) in Aspergillus niger by coexpression of the Penicillium italicum eburicol 14α-demethylase (cyp51) and the A. niger cytochrome P450 reductase (cprA) genes

Brink, Hans J M van den; Nistelrooy, H.J.G.M. van; Waard, M.A. de; Hondel, Cees A. M. J. J. van den; Gorcom, R.F.M. van

doi:10.1016/0168-1656(96)01403-4

Cited by 24 publications

(18 citation statements)

References 19 publications

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“…This indicates that, at least in these strains, mutations in the CYP51 gene are not involved in decreased susceptibility to cyproconazole. However, overexpression of CYP51, as observed in strain I323E1, could contribute to decreased susceptibility (15,37). In summary the data described here suggest that in laboratory strains of M. graminicola, multiple mechanisms contribute to the variation in azole susceptibility.…”

Section: Discussionmentioning

confidence: 78%

“…Resistance to azole antifungal agents can be caused by alterations in sterol biosynthesis (20), mutations of the P450 14DM target site (19,32), or increased levels of expression of the P450 14DM -encoding gene, CYP51 (15,37). Another important resistance mechanism is reduction of the intracellular concentration of the antifungal agent by means of an increased active efflux system.…”

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confidence: 99%

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ABC Transporters and Azole Susceptibility in Laboratory Strains of the Wheat Pathogen Mycosphaerella graminicola

Zwiers

Stergiopoulos

Nistelrooy

et al. 2002

Antimicrob Agents Chemother

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Laboratory strains of Mycosphaerella graminicola with decreased susceptibilities to the azole antifungal agent cyproconazole showed a multidrug resistance phenotype by exhibiting cross-resistance to an unrelated chemical, cycloheximide or rhodamine 6G, or both. Decreased azole susceptibility was found to be associated with either decreased or increased levels of accumulation of cyproconazole. No specific relationship could be observed between azole susceptibility and the expression of ATP-binding cassette (ABC) transporter genes MgAtr1 to MgAtr5 and the sterol P450 14␣-demethylase gene, CYP51. ABC transporter MgAtr1 was identified as a determinant in azole susceptibility since heterologous expression of the protein reduced the azole susceptibility of Saccharomyces cerevisiae and disruption of MgAtr1 in one specific M. graminicola laboratory strain with constitutive MgAtr1 overexpression restored the level of susceptibility to cyproconazole to wild-type levels. However, the level of accumulation in the mutant with an MgAtr1 disruption did not revert to the wild-type level. We propose that variations in azole susceptibility in laboratory strains of M. graminicola are mediated by multiple mechanisms.

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Section: Discussionmentioning

confidence: 78%

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confidence: 99%

ABC Transporters and Azole Susceptibility in Laboratory Strains of the Wheat Pathogen Mycosphaerella graminicola

Zwiers

Stergiopoulos

Nistelrooy

et al. 2002

Antimicrob Agents Chemother

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“…Therefore, reduced azole susceptibility is to be expected in the Nigri group. Resistance mechanisms for the Nigri group have not been elucidated to our knowledge, but azole resistance has been associated with amplification of cypA in an engineered laboratory strain of A. niger (28). Further research is needed to clarify these important issues.…”

Section: Resultsmentioning

confidence: 99%

Wild-Type MIC Distributions and Epidemiological Cutoff Values for the Triazoles and Six Aspergillus spp. for the CLSI Broth Microdilution Method (M38-A2 Document)

et al. 2010

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Among the filamentous (mold) fungal infections, those caused by Aspergillus fumigatus and other Aspergillus spp. are the most common; these infections are associated with high morbidity and mortality, especially in the immunocompromised host (3,7,15,33). The triazoles itraconazole, voriconazole, and posaconazole have a broad spectrum of in vitro activity against molds and are important therapeutic agents for the systemic treatment and prevention of severe mold infections, including aspergillosis (33). Although acquired azole resistance in Aspergillus spp. has been documented since the late 1990s (8), it was uncommon. However, these reports have increased in the last few years, especially in Europe (4, 13, 24, 25, 31). The azoles act by blocking the pathway of ergosterol biosynthesis, specifically the enzymes 14-␣-sterol demethylases A and B. These cytochrome enzymes are encoded by cyp51 (A and B) genes in A. fumigatus and other Aspergillus spp. (19). More importantly, multiazole resistance or cross-resistance has been associated with point mutations in the cyp51A gene in A. fumigatus by substitution of the glycine at position 54 and methionine at position 220 by different amino acids (4, 9, 12), but substitution of L98H and 2 copies of 34 bp in the cyp51A promoter and other mutations also have been identified (13,16,20,25,31). The TR/L98H point mutation has been responsible for an increased level of cyp51A expression (25,29,31), and several mutations have been associated with patient failure on triazole treatment (13, 29, 31); however, other host and drug factors cannot be ignored (e.g., azole bioavailability).The Clinical and Laboratory Standards Institute (CLSI) has developed a reference broth microdilution method for antifungal susceptibility testing of molds (CLSI M38-A2 document) (5). The availability of reference methodologies has enabled the recognition of the complexity of cross-resistance among triazoles (9,18,20,22,24,25) and the proposal for epidemiologic cutoff values (ECVs) for A. fumigatus and itraconazole, posaconazole, and voriconazole by both CLSI (22) and the European Committee of Antibiotic Susceptibility Testing (AFST-EUCAST) (24) methodologies. Clinical breakpoints are not available for mold testing by the CLSI methodology versus any antifungal agent. However, breakpoints based on MIC distributions, pharmacokinetic and pharmacodynamic (PK/PD) parameters, animal data, and clinical experience have been proposed for the EUCAST reference method for A. fumigatus and the three triazoles (30). In the absence of clinical breakpoints, ECVs could help to characterize the susceptibility of Aspergillus isolates to itraconazole, posaconazole, and voriconazole and to monitor the emergence of strains with mutations in the cyp51A gene and/or reduced antifungal triazole

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“…These high triazole MICs are a concern because the A. niger species complex is more frequently involved in pulmonary aspergillosis. Molecular resistance mechanisms have not been identified for the A. niger species complex, but azole resistance was correlated with the multiplication of cyp51A in an engineered laboratory strain of this species (38)(39)(40). Two cyp51 genes were reported in A. terreus species complex isolates, and more recently, a Cyp51Ap M217I alteration was found in isolates with elevated EUCAST itraconazole MICs (1 to 2 g/ml), but such MICs were also found in the absence of alterations; isavuconazole was not evaluated in that study (41).…”

Section: Resultsmentioning

confidence: 99%

Multicenter Study of Isavuconazole MIC Distributions and Epidemiological Cutoff Values for Aspergillus spp. for the CLSI M38-A2 Broth Microdilution Method

Espinel-Ingroff

Chowdhary

González

et al. 2013

Antimicrob Agents Chemother

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Epidemiological cutoff values (ECVs) were established for the new triazole isavuconazole and Aspergillus species wild-type (WT) MIC distributions (organisms in a species-drug combination with no detectable acquired resistance mechanisms) that were defined with 855 Aspergillus fumigatus, 444 A. flavus, 106 A. nidulans, 207 A. niger, 384 A. terreus, and 75 A. versicolor species complex isolates; 22 Aspergillus section Usti isolates were also included. CLSI broth microdilution MIC data gathered in Europe, India, Mexico, and the United States were aggregated to statistically define ECVs. ECVs were 1 g/ml for the A. fumigatus species complex, 1 g/ml for the A. flavus species complex, 0.25 g/ml for the A. nidulans species complex, 4 g/ml for the A. niger species complex, 1 g/ml for the A. terreus species complex, and 1 g/ml for the A. versicolor species complex; due to the small number of isolates, an ECV was not proposed for Aspergillus section Usti. These ECVs may aid in detecting non-WT isolates with reduced susceptibility to isavuconazole due to cyp51A (an A. fumigatus species complex resistance mechanism among the triazoles) or other mutations.

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Increased resistance to 14α-demethylase inhibitors (DMIs) in Aspergillus niger by coexpression of the Penicillium italicum eburicol 14α-demethylase (cyp51) and the A. niger cytochrome P450 reductase (cprA) genes

Cited by 24 publications

References 19 publications

ABC Transporters and Azole Susceptibility in Laboratory Strains of the Wheat Pathogen Mycosphaerella graminicola

ABC Transporters and Azole Susceptibility in Laboratory Strains of the Wheat Pathogen Mycosphaerella graminicola

Wild-Type MIC Distributions and Epidemiological Cutoff Values for the Triazoles and Six Aspergillus spp. for the CLSI Broth Microdilution Method (M38-A2 Document)

Multicenter Study of Isavuconazole MIC Distributions and Epidemiological Cutoff Values for Aspergillus spp. for the CLSI M38-A2 Broth Microdilution Method

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