Multiple
            <i>cyp51A</i>
            -Based Mechanisms Identified in Azole-Resistant Isolates of Aspergillus fumigatus from China

Liu, Musang; Zeng, Rong; Zhang, Lili; Li, Dongmei; Lv, Guixia; Shen, Ya; Zheng, Hailin; Zhang, Qiangqiang; Zhao, Jingjun; Zheng, Nan; Liu, Weida

doi:10.1128/aac.00003-15

Cited by 50 publications

(43 citation statements)

References 43 publications

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“…Both the strain NO.3 (parent strain) and mutant strain 3-339 harbor amino acid mutation N248K in Cyp51A (Table 1). In fact, N248K had been found in many azole-susceptible A. fumigatus strains, and it is believed that this site does not correlate with drug resistance (Liu et al, 2015). Therefore, we next focused on whether V436A and Y433N mutations analyzed by gene sequencing confer resistance to azole.…”

Section: A Predicted 3d Structural Model Displays a Possible Resistanmentioning

confidence: 99%

Uncovering New Mutations Conferring Azole Resistance in the Aspergillus fumigatus cyp51A Gene

et al. 2020

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The opportunistic pathogen Aspergillus fumigatus has developed worldwide resistance to azoles largely through mutations in cytochromeP450 enzyme Cyp51. In this study, we indicated that in vitro azole situation results in emergence of azole-resistant mutations. There are previously identified azole-resistant cyp51A mutations (M220K, M220I, M220R, G54E and G54W mutations) and we successfully identified in this study two new mutations (N248K/V436A, Y433N substitution) conferring azole resistance among 18 independent stable azole-resistant isolates. The Galleria mellonella model of A. fumigatus infection experiment verified that Cyp51A mutations N248K/V436A and Y433N reduce efficacy of azole therapy. In addition, a predicted Cyp51A 3D structural model suggested that Y433N mutation causes the reduced affinities between drug target Cyp51A and azole antifungals. This study suggests that drug selection pressure make it possible to isolate unidentified cyp51A mutations conferring azole resistance in A. fumigatus.

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Section: A Predicted 3d Structural Model Displays a Possible Resistanmentioning

confidence: 99%

Uncovering New Mutations Conferring Azole Resistance in the Aspergillus fumigatus cyp51A Gene

et al. 2020

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“…The emergence of A. fumigatus harboring TR 34 /L98H/S297T/F495I mutation in China was first reported from a global surveillance study conducted in 2008 and 2009; all eight of the resistant isolates originated from different centers in Hangzhou from eastern China (12). In 2015, three clinical A. fumigatus isolates harboring TR 34 /L98H/S297T/F495I or TR 34 / L98H mutations were identified in Fujian, Nanjing, and Shanghai, respectively (13). All three cities are located in the east or southeast of China.…”

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Epidemiology and Molecular Characterizations of Azole Resistance in Clinical and Environmental Aspergillus fumigatus Isolates from China

Chen

Zhao

et al. 2016

Antimicrob Agents Chemother

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i Azole resistance in Aspergillus fumigatus has emerged as a worldwide public health problem. We sought here to demonstrate the occurrence and characteristics of azole resistance in A. fumigatus from different parts of China. A total of 317 clinical and 144 environmental A. fumigatus isolates from 12 provinces were collected and subjected to screening for azole resistance. Antifungal susceptibility, cyp51A gene sequencing, and genotyping were carried out for all suspected azole-resistant isolates and a subset of azole-susceptible isolates. As a result, 8 (2.5%) clinical and 2 (1.4%) environmental A. fumigatus isolates were identified as azole resistant. Five azole-resistant strains exhibit the TR 34 /L98H mutation, whereas four carry the TR 34 /L98H/S297T/F495I mutation in the cyp51A gene. Genetic typing and phylogenetic analysis showed that there was a worldwide clonal expansion of the TR 34 / L98H isolates, while the TR 34 /L98H/S297T/F495I isolates from China harbored a distinct genetic background with resistant isolates from other countries. High polymorphisms existed in the cyp51A gene that produced amino acid changes among azolesusceptible A. fumigatus isolates, with N248K being the most common mutation. These data suggest that the wide distribution of azole-resistant A. fumigatus might be attributed to the environmental resistance mechanisms in China.

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“…This approach not only captures correct electrostatic effects but it is also capable of dynamic ligand exchange with the environment and maintaining the correct number of ligand donors [20]. MD simulations performed in this study further the biological relevance and understanding of azole antifungal drug resistance from the single amino acid mutation, L98H, far from the buried active site [21,22].…”

Section: Introductionmentioning

confidence: 77%

Simulations ofCYP51AfromAspergillus fumigatusin a model bilayer provide insights into triazole drug resistance

Nash

Rhodes

2016

Preprint

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Azole antifungal drugs target CYP51A in Aspergillus fumigatus by binding with the active site of the protein, blocking ergosterol biosynthesis. Resistance to azole anti-fungal drugs is now common, with a leucine to histidine amino acid substitution at position 98 the most frequent, conferring resistance to itraconazole. In this study, we create a homology model of CYP51A using a recently published crystal structure of the paralog protein CYP51B.The derived structures, wild-type and L98H mutant, are positioned within a lipid membrane bilayer and subjected to molecular dynamics simulations in order improve the accuracy of both models. The structural analysis from our simulations suggests a decrease in active site surface from the formation of hydrogen bonds between the histidine substitution and neighbouring polar side chains, potentially preventing the binding of azole drugs. This study yields a biologically relevant structure and set dynamics of the A. fumigatus Lanosterol 14 alpha-demethylase enzyme and provides further insight into azole antifungal drug resistance. 2All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

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Multiple cyp51A -Based Mechanisms Identified in Azole-Resistant Isolates of Aspergillus fumigatus from China

Cited by 50 publications

References 43 publications

Uncovering New Mutations Conferring Azole Resistance in the Aspergillus fumigatus cyp51A Gene

Uncovering New Mutations Conferring Azole Resistance in the Aspergillus fumigatus cyp51A Gene

Epidemiology and Molecular Characterizations of Azole Resistance in Clinical and Environmental Aspergillus fumigatus Isolates from China

Simulations ofCYP51AfromAspergillus fumigatusin a model bilayer provide insights into triazole drug resistance

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