Mutations in the cyp51A gene and susceptibility to itraconazole in Aspergillus fumigatus serially isolated from a patient with lung aspergilloma

Chen, Jian; Li, Houmin; Li, Ruoyu; Bu, Dingfang; Wan, Zhe

doi:10.1093/jac/dkh507

Cited by 173 publications

(150 citation statements)

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“…For isolates with reduced susceptibility to itraconazole and voriconazole (MIC > 2 mg l À1 ), according to CLSI breakpoints (Verweij et al, 2009a), the whole CYP51A gene was amplified, using three pairs of primers (Chen et al, 2005). The primers used were as follows: CYP1-L (5¢-CACCCTCCCTGTGTCTCCT-3¢), CYP1-R (5¢-AGCCTTGAAAGTT-CGGTGAA-3¢), CYP2-L (5¢-CATGTGCCACTTATTGAGAAGG-3¢), C YP2-R (5¢-CCTTGCGCATGATAGAGTGA-3¢), CYP3-L (5¢-TTCC TCCGCTCCAGTACAAG-3¢) and CYP3-R (5¢-CCTTTGAAGTCC TCGATGGT-3¢) (Chen et al, 2005).…”

Section: Methodsmentioning

confidence: 99%

“…The primers used were as follows: CYP1-L (5¢-CACCCTCCCTGTGTCTCCT-3¢), CYP1-R (5¢-AGCCTTGAAAGTT-CGGTGAA-3¢), CYP2-L (5¢-CATGTGCCACTTATTGAGAAGG-3¢), C YP2-R (5¢-CCTTGCGCATGATAGAGTGA-3¢), CYP3-L (5¢-TTCC TCCGCTCCAGTACAAG-3¢) and CYP3-R (5¢-CCTTTGAAGTCC TCGATGGT-3¢) (Chen et al, 2005). Each fragment was sequenced from both ends.…”

Section: Methodsmentioning

confidence: 99%

“…Additionally, in a worldwide survey of medical centers, a resistance rate of 5.8 % was reported, with most resistant isolates reported from China (Bowyer & Denning, 2014). One of the major mechanisms involved in the azole resistance of A. fumigatus is the modification of sterol 14a-demethylation, which is a key enzyme in the ergosterol biosynthetic pathway, encoded by CYP51A and CYP51B genes (Chen et al, 2005;Gulshan & Moye-Rowley, 2007). In fact, mutations at codons TR 34 /L98H, G54, M220, G138C and G432C have been identified in azole-resistant A. fumigatus strains (Chen et al, 2005;Gulshan & Moye-Rowley, 2007).…”

Section: Introductionmentioning

confidence: 99%

“…One of the major mechanisms involved in the azole resistance of A. fumigatus is the modification of sterol 14a-demethylation, which is a key enzyme in the ergosterol biosynthetic pathway, encoded by CYP51A and CYP51B genes (Chen et al, 2005;Gulshan & Moye-Rowley, 2007). In fact, mutations at codons TR 34 /L98H, G54, M220, G138C and G432C have been identified in azole-resistant A. fumigatus strains (Chen et al, 2005;Gulshan & Moye-Rowley, 2007). Over 90 % of azole-resistant A. fumigatus isolates harbour a leucine-to-histidine substitution at codon 98, along with a 34 bp tandem repeat in the CYP51A promoter region.…”

Section: Introductionmentioning

confidence: 99%

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High prevalence of clinical and environmental triazole-resistant Aspergillus fumigatus in Iran: is it a challenging issue?

Nabili

Shokohi

Moazeni

et al. 2016

Journal of Medical Microbiology

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Triazole antifungal agents are the mainstay of aspergillosis treatment. As highlighted in numerous studies, the global increase in the prevalence of triazole resistance could hamper the management of aspergillosis. In the present three-year study, 513 samples (213 clinical and 300 environmental samples) from 10 provinces of Iran were processed and screened in terms of azole resistance (4 and 1 mg l À1 of itraconazole and voriconazole, respectively), using selective plates. Overall, 150 A. fumigatus isolates (71 clinical and 79 environmental isolates) were detected. The isolates were confirmed by partial sequencing of the b-tubulin gene. Afterwards, in vitro antifungal susceptibility tests against triazole agents were performed, based on the Clinical and Laboratory Standards Institute (CLSI) M38-A2 document. The CYP51A gene was sequenced in order to detect mutations. The MIC of itraconazole against 10 (6.6 %) strains, including clinical (n=3, 4.2 %) and environmental (n=7, 8.8 %) strains, was higher than the breakpoint and epidemiological cut-off value. Based on the findings, the prevalence of azole-resistant A. fumigatus in Iran has increased remarkablyfrom 3.3 % to 6.6 % in comparison with earlier epidemiological research. Among resistant isolates, TR 34 /L98H mutations in the CYP51A gene were the most prevalent (n=8, 80 %), whereas other point mutations (F46Y, G54W, Y121F, G138C, M172V, F219C, M220I, D255E, T289F, G432C and G448S mutations) were not detected. Although the number of patients affected by azole-resistant A. fumigatus isolates was limited, strict supervision of clinical azole-resistant A. fumigatus isolates and persistent environmental screening of azole resistance are vital to the development of approaches for the management of azole resistance in human pathogenic fungi.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

High prevalence of clinical and environmental triazole-resistant Aspergillus fumigatus in Iran: is it a challenging issue?

Nabili

Shokohi

Moazeni

et al. 2016

Journal of Medical Microbiology

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show abstract

“…In A. fumigatus, target site alterations are the most commonly reported resistance mechanism, with over 30 cyp51A mutations identified . Resistance can emerge in response to azole therapy Howard et al 2009), and the causative mechanism can change over the course of infection (Chen et al 2005;Howard et al 2009). The most commonly reported Cyp51A substitutions that confer acquired resistance are at codons 54 and 220.…”

Section: Assessing Resistance Factorsmentioning

confidence: 99%

Mechanisms of Antifungal Drug Resistance

Cowen

Sanglard

Howard

et al. 2014

Cold Spring Harb Perspect Med

435

361

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Antifungal therapy is a central component of patient management for acute and chronic mycoses. Yet, treatment choices are restricted because of the sparse number of antifungal drug classes. Clinical management of fungal diseases is further compromised by the emergence of antifungal drug resistance, which eliminates available drug classes as treatment options. Once considered a rare occurrence, antifungal drug resistance is on the rise in many high-risk medical centers. Most concerning is the evolution of multidrug-resistant organisms refractory to several different classes of antifungal agents, especially among common Candida species. The mechanisms responsible are mostly shared by both resistant strains displaying inherently reduced susceptibility and those acquiring resistance during therapy. The molecular mechanisms include altered drug affinity and target abundance, reduced intracellular drug levels caused by efflux pumps, and formation of biofilms. New insights into genetic factors regulating these mechanisms, as well as cellular factors important for stress adaptation, provide a foundation to better understand the emergence of antifungal drug resistance.

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The effect of biosynthesized selenium nanoparticles on the expression of CYP51A and HSP90 antifungal resistance genes in Aspergillus fumigatus and Aspergillus flavus

Bafghi

Nazari

Darroudi

et al. 2021

Biotechnology Progress

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The application of biological nanoparticles (NPs) can be considered as a way to overcome the problem of antifungal resistance in pathogenic fungi. This study takes a new approach to biosynthesized NPs influence on the expression of CYP51A and HSP90 antifungal resistance genes in Aspergillus fumigatus and A. flavus, and comparison with antifungal agents. Selenium NPs (Se-NPs) were biosynthesized using Aspergillus strains and their production was proved by several methods including, UV-Vis, XRD, FTIR, FESEM, and EDX techniques. The minimum inhibitory concentrations (MICs) of Aspergillus strains were determined using the CLSI M38-A2 broth microdilution method. The differences in expression levels of CYP51A and HSP90 genes were examined between untreated and treated of A. fumigatus and A. flavus using itraconazole and amphotericin B and biosynthesized Se-NPs through real-time PCR. After confirming the results of NPs synthesis, the MIC of itraconazole and amphotericin B against A. fumigatus and A. flavus was 4 μg/ml. Based on the real-time PCR results, the obtained ΔΔCTs for these strains were À0.18, À1.46, and À1.14. Whereas the MIC values for treated samples with Se-NPs have decreased to 0.5 μg/ml, and the ΔΔCTs for these were À0.25, À1.76, and À1.68. The expression of CYP51A and HSP90 genes was significantly down-regulated through the use of Se-NPs against A. fumigatus and A. flavus.

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Mutations in the cyp51A gene and susceptibility to itraconazole in Aspergillus fumigatus serially isolated from a patient with lung aspergilloma

Abstract: We conclude that resistance of A. fumigatus to itraconazole occurred in a patient treated with the drug, and the resistance may result from mutations in the cyp51A gene-the gene encoding the target enzyme for itraconazole.

Cited by 173 publications

References 32 publications

High prevalence of clinical and environmental triazole-resistant Aspergillus fumigatus in Iran: is it a challenging issue?

High prevalence of clinical and environmental triazole-resistant Aspergillus fumigatus in Iran: is it a challenging issue?

Mechanisms of Antifungal Drug Resistance

The effect of biosynthesized selenium nanoparticles on the expression of CYP51A and HSP90 antifungal resistance genes in Aspergillus fumigatus and Aspergillus flavus

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