Molecular characterisation of cyp51A and cyp51B genes coding for P450 14α-lanosterol demethylases A (CYP51Ap) and B (CYP51Bp) from voriconazole-resistant laboratory isolates of Aspergillus flavus

Krishnan-Natesan, Suganthini; Chandrasekar, Pranatharthi H.; Alangaden, George; Manavathu, Elias K.

doi:10.1016/j.ijantimicag.2008.06.018

Cited by 46 publications

(51 citation statements)

References 22 publications

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“…As for A. fumigatus, cyp51Ap gene modifications also appeared to be responsible for in vitro azole resistance in this species. Therefore, extensive use of voriconazole prophylaxis in immunocompromised patients may lead to the selection of voriconazole-resistant A. flavus isolates (16). To our knowledge, data regarding triazole molecular resistance mechanisms are not available for A. terreus, but the presence of the two cyp51 genes also was reported for this species as early as those for the other species (19).…”

Section: Resultsmentioning

confidence: 96%

“…The presence of cyp51 genes in A. flavus has been reported since 2001 (19 [16]). As for A. fumigatus, cyp51Ap gene modifications also appeared to be responsible for in vitro azole resistance in this species.…”

Section: Resultsmentioning

confidence: 99%

“…The link between single and/or multiple triazole resistance with either point mutations and/or treatment failure has been demonstrated for A. fumigatus and A. flavus (12,13,16,18,19,20,24,25,29,31). In our study, we analyzed triazole crossresistance using data from the 86 isolates for which itraconazole MICs were Ն4 g/ml.…”

Section: Resultsmentioning

confidence: 99%

“…(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).…”

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confidence: 99%

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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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Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…The authors were able to recapitulate the substitution-mediated resistance phenotype using site-directed gene mutagenesis. In addition to the anomaly in cyp51C, Krishnan-Natesan et al also reported other genetic aberrations in cyp51A and cyp51B that may contribute to triazole resistance in A. flavus [69]. However, these resistance-associated mutations have not yet been confirmed experimentally.…”

Section: A Triazole Resistant Aspergillimentioning

confidence: 99%

An Invisible Threat: Mutation-Mediated Resistance to Triazole Drugs in Aspergillus

Pham

Lockhart

2012

Curr Fungal Infect Rep

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Aspergillosis has emerged as an important contributor to infection-related morbidity and mortality in susceptible populations. This comes at a time when we are also seeing an increase in the vulnerable populations themselves. At the same time, some parts of the world are reporting an increased incidence of aspergillosis refractory to triazole therapy. Resistance to triazole drugs may have major implications for aspergillosis management since our antifungal armamentarium is limited. This review gives an overview of populations at risk of developing aspergillosis and highlights resistance mechanisms that may contribute to morbidity and mortality in these vulnerable populations.

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Antifungal Resistance: Cellular and Molecular Mechanisms

Araújo¹,

Espinel-Ingroff²

2010

Combating Fungal Infections

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Molecular characterisation of cyp51A and cyp51B genes coding for P450 14α-lanosterol demethylases A (CYP51Ap) and B (CYP51Bp) from voriconazole-resistant laboratory isolates of Aspergillus flavus

Cited by 46 publications

References 22 publications

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

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

An Invisible Threat: Mutation-Mediated Resistance to Triazole Drugs in Aspergillus

Antifungal Resistance: Cellular and Molecular Mechanisms

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