Multi-azole resistance in Aspergillus fumigatus

Howard, Susan J.; Webster, Ian; Moore, Caroline B.; Gardiner, R. E.; Park, Steven; Perlin, David S.; Denning, David W.

doi:10.1016/j.ijantimicag.2006.08.017

Cited by 190 publications

(172 citation statements)

References 24 publications

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“…A high-throughput multiplex reverse transcription (RT)-PCR developed to identify mutations in A. fumigatus cyp51A revealed that nearly 50% of clinical isolates or laboratory-derived mutants with reduced susceptibility to itraconazole had a G54 mutation (36). Other less commonly identified mutations that are involved in A. fumigatus azole resistance include methionine 220 (M220) and glycine 138 (G138) mutations (234,377). More recently, alternative mutations have emerged as a prevalent mechanism of azole resistance in A. fumigatus.…”

Section: Alteration Of the Drug Targetmentioning

confidence: 99%

Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

Shapiro

Robbins

Cowen

2011

Microbiol Mol Biol Rev

474

547

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SUMMARY Pathogenic fungi have become a leading cause of human mortality due to the increasing frequency of fungal infections in immunocompromised populations and the limited armamentarium of clinically useful antifungal drugs. Candida albicans , Cryptococcus neoformans , and Aspergillus fumigatus are the leading causes of opportunistic fungal infections. In these diverse pathogenic fungi, complex signal transduction cascades are critical for sensing environmental changes and mediating appropriate cellular responses. For C. albicans , several environmental cues regulate a morphogenetic switch from yeast to filamentous growth, a reversible transition important for virulence. Many of the signaling cascades regulating morphogenesis are also required for cells to adapt and survive the cellular stresses imposed by antifungal drugs. Many of these signaling networks are conserved in C. neoformans and A. fumigatus , which undergo distinct morphogenetic programs during specific phases of their life cycles. Furthermore, the key mechanisms of fungal drug resistance, including alterations of the drug target, overexpression of drug efflux transporters, and alteration of cellular stress responses, are conserved between these species. This review focuses on the circuitry regulating fungal morphogenesis and drug resistance and the impact of these pathways on virulence. Although the three human-pathogenic fungi highlighted in this review are those most frequently encountered in the clinic, they represent a minute fraction of fungal diversity. Exploration of the conservation and divergence of core signal transduction pathways across C. albicans , C. neoformans , and A. fumigatus provides a foundation for the study of a broader diversity of pathogenic fungi and a platform for the development of new therapeutic strategies for fungal disease.

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Section: Alteration Of the Drug Targetmentioning

confidence: 99%

Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

Shapiro

Robbins

Cowen

2011

Microbiol Mol Biol Rev

474

547

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“…However it was not possible to amplify the other isolates with the primer pair employed. This is because A. niger is a species complex consisting of numerous different strains [14] and several other primer pairs would have to be used in order to amplify the other isolates [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29].…”

Section: Discussionmentioning

confidence: 99%

Determination of Azole Antifungal Drug Resistance Mechanisms Involving Cyp51a Gene in Clinical Isolates of Aspergillus fumigatus and Aspergillus niger

Rajendran¹,

Khaithir²,

Santhanam³

2016

Mycology

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Aims: The main aim of this research is to investigate azole resistance mechanisms in A. fumigatus and A. niger which involve Cyp51A gene that encodes 14-α sterol demethylase enzyme. Methodology and results:Itraconazole susceptibility was determined through E-test method. A conventional PCR method was used to amplify and sequence Cyp51A gene in fungal DNA, to detect the presence of gene mutations. Real-time PCR method was applied to determine overexpression of Cyp51A gene in A. fumigatus and A. niger isolates. Susceptibility test found that 3/13 (23.1%) A. fumigatus and 7/23 (30.4%) A. niger isolates were resistant to Itraconazole, with minimum inhibitory concentrations (MICs) of 2.5 µg/ml to 3.0 µg/ml. Sequencing of A. fumigatus DNA showed presence of L98H mutation in 7/13 (53.8%) and M220 mutation in 3/13 (23%) isolates. Whereas, sequencing of A. niger DNA detected the presence of G427S mutation in 3/23 (13%) isolates. Tandem Repeat mutation was not detected in all A. fumigatus and A. niger isolates. Only M220 mutation showed significant correlation (r (13)=0.041038, p<0.05) with Itraconazole antifungal resistance in A. fumigatus isolates while L98H mutation was not involved. G427S mutation also showed correlation (r (15)=0.038434, p<0.05) with Itraconazole antifungal resistance in A. niger isolates. A higher level of Cyp51A gene expression was detected in 4/8 (50%) A. fumigatus isolates and 7/12 (58.3%) A. niger isolates. Resistant isolates more often showed higher level of Cyp51A gene expression compared to susceptible isolates; however the difference in level of expression between resistant isolates and susceptible isolates is not significant. This may be due to similar MIC values in resistant and susceptible isolates.Conclusion, significance and impact of study: In conclusion the level of azole resistance in A. fumigatus and A. niger isolates in Malaysia is low and mutations in Cyp51A gene may contribute towards Itraconazole antifungal resistance, however other factors may also be involved.

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“…A total of 49 A. fumigatus strains (43 clinical strains) were obtained from the Mycelial Collection of the Spanish National Center for Microbiology. Eleven strains belong to the Public Health Research Institute (PHRI) collection, eight of them were A. fumigatus clinical isolates (kindly provided by D. Denning, Manchester University, Manchester, United Kingdom) (18) and three laboratory-derived mutants (33). Moreover, 10 A. fumigatus with known cyp51A mutations (G54V, G54E, G54R, G54W, TR-L98H, G138C, M220V, M220K, M220T, and M220I) (17,27) or isolated with the Q-Biogene FastDNA kit (Irvine, CA) according to the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

“…are highly susceptible to these drugs (10). However, as the incidence of IA infections rise (25), there are an increasing number of reports of secondary acquired resistance in clinical strains of A. fumigatus strains (3,6,8,9,13,18,23,28,29,31). It was recently reported in The Netherlands that, since 2002, a significant number of clinical A. fumigatus isolates with multiple resistance to VRC, ITC, ravuconazole (RVC), and PSC have been detected (44).…”

mentioning

confidence: 99%

“…In A. fumigatus there are two distinct but related 14-␣ sterol demethylase (cyp51) proteins encoded by cyp51A and cyp51B (27), although only mutations in Cyp51A are important for clinical resistance. These mutations confer several different susceptibility profiles: (i) resistance to ITC and PSC associated with amino acid substitutions at Cyp51A glycine 54 (Gly 54) (9,23,33); (ii) a pattern of resistance to ITC and high VRC, RVC, and PSC MICs (strains exhibiting this susceptibility profile harbor amino acid substitutions at methionine 220 [Met 220]) (3,28); (iii) a pattern of azole cross-resistance associated with higher cyp51A expression produced by a tandem repeat (TR) of a 34-bp sequence in the cyp51A gene promoter in combination with an amino acid substitution at Cyp51A leucine 98 (TR-L98H) (29,44); and (iv) a triazole cross-resistance related to an amino acid change at Cyp51A glycine 138 to cysteine (G138C) (18).…”

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confidence: 99%

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Rapid Detection of Triazole Antifungal Resistance in Aspergillus fumigatus

et al. 2008

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Triazole resistance in Aspergillus fumigatus is an uncommon but rising phenomenon. Susceptibility testing is rarely performed and can take 48 h or longer, which is an impediment to effective therapy. Molecular diagnostic probing of well-defined resistance mechanisms, which serve as surrogate markers, provides an alternative approach to rapidly (within hours) and efficiently identify resistant strains. The mechanisms of triazole resistance in A. fumigatus are limited to amino acid substitutions in the drug target Cyp51A and include amino acid substitutions at the positions Gly 54, Gly 138, Met 220, and Leu 98, coupled with a tandem repetition in the gene promoter. We report the development of a real-time PCR assay utilizing molecular beacons to assess triazole resistance markers in A. fumigatus. When combined in a multiplex platform, the assay provides a comprehensive evaluation of drug resistance in A. fumigatus.

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Multi-azole resistance in Aspergillus fumigatus

Cited by 190 publications

References 24 publications

Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

Determination of Azole Antifungal Drug Resistance Mechanisms Involving Cyp51a Gene in Clinical Isolates of Aspergillus fumigatus and Aspergillus niger

Rapid Detection of Triazole Antifungal Resistance in Aspergillus fumigatus

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