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

Peiying Chen; Musang Liu; Musang Liu; Qiuqiong Zeng; Zheng Zhang; Weida Liu; Weida Liu; Hong Sang; Ling Lu

doi:10.3389/fmicb.2019.03127

Frontiers in Microbiology (Jan 2020)

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

Peiying Chen,
Musang Liu,
Musang Liu,
Qiuqiong Zeng,
Zheng Zhang,
Weida Liu,
Weida Liu,
Hong Sang,
Ling Lu

Affiliations

Peiying Chen: Department of Dermatology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China
Musang Liu: Department of Medical Mycology, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
Musang Liu: Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Nanjing, China
Qiuqiong Zeng: Department of Dermatology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China
Zheng Zhang: Department of Dermatology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China
Weida Liu: Department of Medical Mycology, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
Weida Liu: Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Nanjing, China
Hong Sang: Department of Dermatology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China
Ling Lu: Jiangsu Key Laboratory for Microbes and Functional Genomics, Jiangsu Engineering and Technology Research Center for Microbiology, College of Life Sciences, Nanjing Normal University, Nanjing, China

DOI: https://doi.org/10.3389/fmicb.2019.03127
Journal volume & issue: Vol. 10

Abstract

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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.

Published in Frontiers in Microbiology

ISSN: 1664-302X (Online)
Publisher: Frontiers Media S.A.
Country of publisher: Switzerland
LCC subjects: Science: Microbiology
Website: http://www.frontiersin.org/journals/microbiology

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