Azole-resistant aspergillosis

Warris, Adilia

doi:10.1016/j.jinf.2015.04.023

Cited by 20 publications

(15 citation statements)

References 53 publications

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“…Previous studies have verified that azoles are capable of interfering with the activity of 14-␣-lanosterol demethylase to inhibit ergosterol biosynthesis (25). To further analyze the resistance mechanism of two mutations, AfCox10 R243Q and AfCyp51A F219L , we tested and compared the contents of ergosterol and the sterol intermediates in itraconazole-resistant isolates and the parental wild-type strain.…”

Section: Resultsmentioning

confidence: 99%

Screening and Characterization of a Non- cyp51A Mutation in an Aspergillus fumigatus cox10 Strain Conferring Azole Resistance

Wei

Chen

Gao

et al. 2017

Antimicrob Agents Chemother

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The rapid and global emergence of azole resistance in the human pathogen Aspergillus fumigatus has drawn attention. Thus, a thorough understanding of its mechanisms of drug resistance requires extensive exploration. In this study, we found that the loss of the putative calcium-dependent protein-encoding gene algA causes an increased frequency of azole-resistant A. fumigatus isolates. In contrast to previously identified azole-resistant isolates related to cyp51A mutations, only one isolate carries a point mutation in cyp51A (F219L mutation) among 105 independent stable azole-resistant isolates. Through next-generation sequencing (NGS), we successfully identified a new mutation (R243Q substitution) conferring azole resistance in the putative A. fumigatus farnesyltransferase Cox10 (AfCox10) (AFUB_065450). High-performance liquid chromatography (HPLC) analysis verified that the decreased absorption of itraconazole in related Afcox10 mutants is the primary reason for itraconazole resistance. Moreover, a complementation experiment by reengineering the mutation in a parental wild-type background strain demonstrated that both the F219L and R243Q mutations contribute to itraconazole resistance in an algAindependent manner. These data collectively suggest that the loss of algA results in an increased frequency of azole-resistant isolates with a non-cyp51A mutation. Our findings indicate that there are many unexplored non-cyp51A mutations conferring azole resistance in A. fumigatus and that algA defects make it possible to isolate drug-resistant alleles. In addition, our study suggests that genome-wide sequencing combined with alignment comparison analysis is an efficient approach to identify the contribution of single nucleotide polymorphism (SNP) diversity to drug resistance.KEYWORDS Aspergillus fumigatus, azole resistance, cox10, cyp51A, mutation T he filamentous fungus Aspergillus fumigatus, one of the major opportunistic fungal pathogens, causes invasive fungal infections (IFIs) among immunosuppressed patients, with a high mortality rate (1, 2). Currently, azole compounds are the primary clinical therapy drug for IFIs and have been widely used in agriculture as well (3, 4). However, with the emergence of azole-resistant isolates, the efficacy of azole antifungals has been restricted so that azole resistance is becoming a growing public health menace (5-8). Therefore, the identification of genes whose mutations lead to drug resistance can provide a complete understanding of the molecular mechanisms underlying azole resistance.Previous studies verified that the most common mechanisms of resistance to azole antifungals observed in A. fumigatus samples are due to Cyp51A mutations, which

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Section: Resultsmentioning

confidence: 99%

Screening and Characterization of a Non- cyp51A Mutation in an Aspergillus fumigatus cox10 Strain Conferring Azole Resistance

Wei

Chen

Gao

et al. 2017

Antimicrob Agents Chemother

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“…Importantly, patients with CPA require long-term maintenance antifungal therapy to improve symptoms and prevent the recurrence of infection (36,37). The acquisition of azole resistance in A. fumigatus is an emerging public health problem which definitely needs continued surveillance at the national and international levels (9). The main molecular mechanism of azole resistance in A. fumigatus is explained by several mutations in the cyp51A gene (38).…”

Section: Discussionmentioning

confidence: 99%

“…The trend of increases in the rates of azole resistance among A. fumigatus isolates in different regions and patient groups exemplifies the fact that knowledge of the (local) epidemiology of azoleresistant Aspergillus diseases is important for clinical mycology/ microbiology reference laboratories (7)(8)(9). Moreover, rapid and specific molecular methods for the identification of the recently identified azole-resistant A. fumigatus strains can significantly influence a timely decision on patient management (10).…”

mentioning

confidence: 99%

Quantitative Analysis of Single-Nucleotide Polymorphism for Rapid Detection of TR ₃₄ /L98H- and TR ₄₆ /Y121F/T289A-Positive Aspergillus fumigatus Isolates Obtained from Patients in Iran from 2010 to 2014

Mohammadi

Hashemi

Zoll

et al. 2016

Antimicrob Agents Chemother

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gWe employed an endpoint genotyping method to update the prevalence rate of positivity for the TR 34 /L98H mutation (a 34-bp tandem repeat mutation in the promoter region of the cyp51A gene in combination with a substitution at codon L98) and the TR 46 A zole resistance in Aspergillus fumigatus is a global and evolving public health threat which translates into treatment failure (1). Surveillance studies indicate that the incidence of azole resistance is increasing (2-6), with the TR 34 /L98H mutation (a 34-bp tandem repeat mutation in the promoter region of the cyp51A gene in combination with a substitution at codon L98) emerging in multiple European countries and in the Middle East, Asia, and Africa and with a new resistance mechanism, the TR 46 /Y121F/ T289A mutation (a 46-bp tandem repeat mutation in the promoter region of the cyp51A gene in combination with substitutions at codons Y121 and T289), emerging more recently in Europe and India (2-6). We also previously reported the occurrence of the TR 34 /L98H mutation in 3.2% of clinical Aspergillus fumigatus isolates obtained from patients in Iran to the end of 2009 (5).The trend of increases in the rates of azole resistance among A. fumigatus isolates in different regions and patient groups exemplifies the fact that knowledge of the (local) epidemiology of azoleresistant Aspergillus diseases is important for clinical mycology/ microbiology reference laboratories (7-9). Moreover, rapid and specific molecular methods for the identification of the recently identified azole-resistant A. fumigatus strains can significantly influence a timely decision on patient management (10).In our search for a novel, rapid, sensitive, accurate, and highthroughput method for detection and screening of azole resistance in A. fumigatus, we found that endpoint genotyping targeting a single-nucleotide polymorphism (SNP) in the cyp51A gene could provide an option. The quantitative analysis of SNPs has been a reliable method in diagnostic microbiology for identification of a single nucleotide in the genomes of humans (11-15), viruses (16-20), and bacteria (18). In this assay, an extension probe can be simply designed to anneal to the template in a posi-

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“…Until recently, amphotericin B and the triazole posaconazole were the only two systemic antifungals available with good activity against Mucorales . The search for new antifungal agents was propelled by pharmacological limitations of currently available triazole formations, the unfavorable toxicity profile of polyene compounds, and the emergence of resistant strains …”

Section: Introductionmentioning

confidence: 99%

Successful treatment of invasive mucormycosis with isavuconazole in pediatric patients

Barg

Malkiel

Bartuv

et al. 2018

Pediatric Blood & Cancer

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Azole-resistant aspergillosis

Cited by 20 publications

References 53 publications

Screening and Characterization of a Non- cyp51A Mutation in an Aspergillus fumigatus cox10 Strain Conferring Azole Resistance

Screening and Characterization of a Non- cyp51A Mutation in an Aspergillus fumigatus cox10 Strain Conferring Azole Resistance

Quantitative Analysis of Single-Nucleotide Polymorphism for Rapid Detection of TR ₃₄ /L98H- and TR ₄₆ /Y121F/T289A-Positive Aspergillus fumigatus Isolates Obtained from Patients in Iran from 2010 to 2014

Successful treatment of invasive mucormycosis with isavuconazole in pediatric patients

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Azole-resistant aspergillosis

Cited by 20 publications

References 53 publications

Screening and Characterization of a Non- cyp51A Mutation in an Aspergillus fumigatus cox10 Strain Conferring Azole Resistance

Screening and Characterization of a Non- cyp51A Mutation in an Aspergillus fumigatus cox10 Strain Conferring Azole Resistance

Quantitative Analysis of Single-Nucleotide Polymorphism for Rapid Detection of TR 34 /L98H- and TR 46 /Y121F/T289A-Positive Aspergillus fumigatus Isolates Obtained from Patients in Iran from 2010 to 2014

Successful treatment of invasive mucormycosis with isavuconazole in pediatric patients

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Quantitative Analysis of Single-Nucleotide Polymorphism for Rapid Detection of TR ₃₄ /L98H- and TR ₄₆ /Y121F/T289A-Positive Aspergillus fumigatus Isolates Obtained from Patients in Iran from 2010 to 2014