Global Screening of Genomic and Transcriptomic Factors Associated with Phenotype Differences between Multidrug-Resistant and -Susceptible <named-content content-type="genus-species">Candida haemulonii</named-content> Strains

ABSTRACT Candida haemulonii, a close relative of Candida auris, is an emerging pathogen which frequently shows multidrug resistance especially to triazoles, the most used antifungal drugs. The mechanisms of drug resistance in C. haemulonii, however, are largely unknown. Here, we sequenced and annota...

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Autores principales:	Hao Zhang, Yifei Niu, Jingwen Tan, Weixia Liu, Ming-an Sun, Ence Yang, Qian Wang, Ruoyu Li, Yejun Wang, Wei Liu
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Candida haemulonii complex comparative genomics genome multidrug resistance transcriptome Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/0cd4eeee007b4baeb1bca9be8ecec072
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spelling	oai:doaj.org-article:0cd4eeee007b4baeb1bca9be8ecec0722021-12-02T18:39:15ZGlobal Screening of Genomic and Transcriptomic Factors Associated with Phenotype Differences between Multidrug-Resistant and -Susceptible <named-content content-type="genus-species">Candida haemulonii</named-content> Strains10.1128/mSystems.00459-192379-5077https://doaj.org/article/0cd4eeee007b4baeb1bca9be8ecec0722019-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSystems.00459-19https://doaj.org/toc/2379-5077ABSTRACT Candida haemulonii, a close relative of Candida auris, is an emerging pathogen which frequently shows multidrug resistance especially to triazoles, the most used antifungal drugs. The mechanisms of drug resistance in C. haemulonii, however, are largely unknown. Here, we sequenced and annotated the genomes of two reference strains from the C. haemulonii complex, compared the phenotypes, genomes, and transcriptomes of a triazole-susceptible and two triazole-resistant C. haemulonii strains, and identified triazole susceptibility, morphology, fitness, and the major genetic and gene expression differences between the strains. A multidrug efflux gene, CDR1, was recurrently found to be upregulated for expression in triazole-resistant strains. Blocking the activity of Cdr1 increased the susceptibility to triazoles strikingly. Comparative transcriptome analysis also demonstrated impaired cell wall integrity, filamentous growth, and iron homeostasis in triazole-resistant strains. Finally, we also identified a zinc-binding MHR family transcription regulator gene that mutated in triazole-resistant strains spontaneously, contributing to the changes of morphology and, possibly, cell wall integrity between the strains. The study provided important clues for future studies exploring the mechanisms of multidrug resistance and related phenotypic differences of C. haemulonii strains. IMPORTANCE A comprehensive, multi-omic survey was performed to disclose the genetic backgrounds and differences between multidrug-resistant and -susceptible C. haemulonii strains. Genes were identified with mutations or significant expression differences in multidrug-resistant compared to multidrug-susceptible strains, which were mainly involved in multidrug resistance, stress fitness, and morphology. The Cdr1-encoding gene, C. haemulonii 2486 (CH_2486), was expressed at a significantly increased level in multidrug-resistant strains. Functional inhibition experiments further implicated potential roles of CH_2486 in drug resistance. A gene spontaneously mutated in resistant strains, CH_4347, was experimentally validated to influence the morphology of spores, possibly by controlling cell wall integrity.Hao ZhangYifei NiuJingwen TanWeixia LiuMing-an SunEnce YangQian WangRuoyu LiYejun WangWei LiuAmerican Society for MicrobiologyarticleCandida haemulonii complexcomparative genomicsgenomemultidrug resistancetranscriptomeMicrobiologyQR1-502ENmSystems, Vol 4, Iss 6 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Candida haemulonii complex comparative genomics genome multidrug resistance transcriptome Microbiology QR1-502
spellingShingle	Candida haemulonii complex comparative genomics genome multidrug resistance transcriptome Microbiology QR1-502 Hao Zhang Yifei Niu Jingwen Tan Weixia Liu Ming-an Sun Ence Yang Qian Wang Ruoyu Li Yejun Wang Wei Liu Global Screening of Genomic and Transcriptomic Factors Associated with Phenotype Differences between Multidrug-Resistant and -Susceptible <named-content content-type="genus-species">Candida haemulonii</named-content> Strains
description	ABSTRACT Candida haemulonii, a close relative of Candida auris, is an emerging pathogen which frequently shows multidrug resistance especially to triazoles, the most used antifungal drugs. The mechanisms of drug resistance in C. haemulonii, however, are largely unknown. Here, we sequenced and annotated the genomes of two reference strains from the C. haemulonii complex, compared the phenotypes, genomes, and transcriptomes of a triazole-susceptible and two triazole-resistant C. haemulonii strains, and identified triazole susceptibility, morphology, fitness, and the major genetic and gene expression differences between the strains. A multidrug efflux gene, CDR1, was recurrently found to be upregulated for expression in triazole-resistant strains. Blocking the activity of Cdr1 increased the susceptibility to triazoles strikingly. Comparative transcriptome analysis also demonstrated impaired cell wall integrity, filamentous growth, and iron homeostasis in triazole-resistant strains. Finally, we also identified a zinc-binding MHR family transcription regulator gene that mutated in triazole-resistant strains spontaneously, contributing to the changes of morphology and, possibly, cell wall integrity between the strains. The study provided important clues for future studies exploring the mechanisms of multidrug resistance and related phenotypic differences of C. haemulonii strains. IMPORTANCE A comprehensive, multi-omic survey was performed to disclose the genetic backgrounds and differences between multidrug-resistant and -susceptible C. haemulonii strains. Genes were identified with mutations or significant expression differences in multidrug-resistant compared to multidrug-susceptible strains, which were mainly involved in multidrug resistance, stress fitness, and morphology. The Cdr1-encoding gene, C. haemulonii 2486 (CH_2486), was expressed at a significantly increased level in multidrug-resistant strains. Functional inhibition experiments further implicated potential roles of CH_2486 in drug resistance. A gene spontaneously mutated in resistant strains, CH_4347, was experimentally validated to influence the morphology of spores, possibly by controlling cell wall integrity.
format	article
author	Hao Zhang Yifei Niu Jingwen Tan Weixia Liu Ming-an Sun Ence Yang Qian Wang Ruoyu Li Yejun Wang Wei Liu
author_facet	Hao Zhang Yifei Niu Jingwen Tan Weixia Liu Ming-an Sun Ence Yang Qian Wang Ruoyu Li Yejun Wang Wei Liu
author_sort	Hao Zhang
title	Global Screening of Genomic and Transcriptomic Factors Associated with Phenotype Differences between Multidrug-Resistant and -Susceptible <named-content content-type="genus-species">Candida haemulonii</named-content> Strains
title_short	Global Screening of Genomic and Transcriptomic Factors Associated with Phenotype Differences between Multidrug-Resistant and -Susceptible <named-content content-type="genus-species">Candida haemulonii</named-content> Strains
title_full	Global Screening of Genomic and Transcriptomic Factors Associated with Phenotype Differences between Multidrug-Resistant and -Susceptible <named-content content-type="genus-species">Candida haemulonii</named-content> Strains
title_fullStr	Global Screening of Genomic and Transcriptomic Factors Associated with Phenotype Differences between Multidrug-Resistant and -Susceptible <named-content content-type="genus-species">Candida haemulonii</named-content> Strains
title_full_unstemmed	Global Screening of Genomic and Transcriptomic Factors Associated with Phenotype Differences between Multidrug-Resistant and -Susceptible <named-content content-type="genus-species">Candida haemulonii</named-content> Strains
title_sort	global screening of genomic and transcriptomic factors associated with phenotype differences between multidrug-resistant and -susceptible <named-content content-type="genus-species">candida haemulonii</named-content> strains
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/0cd4eeee007b4baeb1bca9be8ecec072
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Global Screening of Genomic and Transcriptomic Factors Associated with Phenotype Differences between Multidrug-Resistant and -Susceptible <named-content content-type="genus-species">Candida haemulonii</named-content> Strains

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