Mutations in <italic toggle="yes">hmg1</italic>, Challenging the Paradigm of Clinical Triazole Resistance in <named-content content-type="genus-species">Aspergillus fumigatus</named-content>

ABSTRACT Aspergillus fumigatus is the predominant pathogen of invasive aspergillosis, a disease state credited with over 200,000 life-threatening infections each year. The triazole class of antifungals are clinically essential to the treatment of invasive aspergillosis, both as frontline and as salv...

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Autores principales:	Jeffrey M. Rybak, Wenbo Ge, Nathan P. Wiederhold, Josie E. Parker, Steven L. Kelly, P. David Rogers, Jarrod R. Fortwendel
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Aspergillus fumigatus HMG-CoA reductase antifungal resistance ergosterol hmg1 triazole Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/1a326c478b58433da1a49105ffc817db
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spelling	oai:doaj.org-article:1a326c478b58433da1a49105ffc817db2021-11-15T15:55:25ZMutations in <italic toggle="yes">hmg1</italic>, Challenging the Paradigm of Clinical Triazole Resistance in <named-content content-type="genus-species">Aspergillus fumigatus</named-content>10.1128/mBio.00437-192150-7511https://doaj.org/article/1a326c478b58433da1a49105ffc817db2019-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00437-19https://doaj.org/toc/2150-7511ABSTRACT Aspergillus fumigatus is the predominant pathogen of invasive aspergillosis, a disease state credited with over 200,000 life-threatening infections each year. The triazole class of antifungals are clinically essential to the treatment of invasive aspergillosis, both as frontline and as salvage therapy. Unfortunately, resistance to the triazoles among A. fumigatus isolates is now increasingly reported worldwide, and a large proportion of this resistance remains unexplained. In this work, we characterize the contributions of previously identified mechanisms of triazole resistance, including mutations in the sterol-demethylase-encoding gene cyp51A, overexpression of sterol-demethylase genes, and overexpression of the efflux pump-encoding gene abcC, among a large collection of highly triazole-resistant clinical A. fumigatus isolates. Upon revealing that these mechanisms alone cannot substantiate the majority of triazole resistance exhibited by this collection, we subsequently describe the identification and characterization of a novel genetic determinant of triazole resistance. Mutations in the 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase-encoding gene, hmg1, were identified in a majority of triazole-resistant clinical isolates in our collection. Introduction of three different hmg1 mutations, predicted to encode residue alterations in the conserved sterol sensing domain of Hmg1, resulted in significantly increased resistance to the triazole class of agents. Additionally, correction of a hmg1 mutation in a pan-triazole-resistant clinical isolate of A. fumigatus with a novel Cas9-ribonucleoprotein-mediated system was shown to restore clinical susceptibility to all triazole agents. Mutations in hmg1 were also shown to lead to the accumulation of ergosterol precursors, such as eburicol, by sterol profiling, while not altering the expression of sterol-demethylase genes. IMPORTANCE Aspergillus fumigatus is the predominant pathogen of invasive aspergillosis, a disease state credited with over 200,000 life-threatening infections annually. The triazole class of antifungals are clinically essential to the treatment of invasive aspergillosis. Unfortunately, resistance to the triazoles among A. fumigatus isolates is now increasingly reported worldwide. In this work, we challenge the current paradigm of clinical triazole resistance in A. fumigatus, by first demonstrating that previously characterized mechanisms of resistance have nominal impact on triazole susceptibility and subsequently identifying a novel mechanism of resistance with a profound impact on clinical triazole susceptibility. We demonstrate that mutations in the HMG-CoA reductase gene, hmg1, are common among resistant clinical isolates and that hmg1 mutations confer resistance to all clinically available triazole antifungals.Jeffrey M. RybakWenbo GeNathan P. WiederholdJosie E. ParkerSteven L. KellyP. David RogersJarrod R. FortwendelAmerican Society for MicrobiologyarticleAspergillus fumigatusHMG-CoA reductaseantifungal resistanceergosterolhmg1triazoleMicrobiologyQR1-502ENmBio, Vol 10, Iss 2 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Aspergillus fumigatus HMG-CoA reductase antifungal resistance ergosterol hmg1 triazole Microbiology QR1-502
spellingShingle	Aspergillus fumigatus HMG-CoA reductase antifungal resistance ergosterol hmg1 triazole Microbiology QR1-502 Jeffrey M. Rybak Wenbo Ge Nathan P. Wiederhold Josie E. Parker Steven L. Kelly P. David Rogers Jarrod R. Fortwendel Mutations in <italic toggle="yes">hmg1</italic>, Challenging the Paradigm of Clinical Triazole Resistance in <named-content content-type="genus-species">Aspergillus fumigatus</named-content>
description	ABSTRACT Aspergillus fumigatus is the predominant pathogen of invasive aspergillosis, a disease state credited with over 200,000 life-threatening infections each year. The triazole class of antifungals are clinically essential to the treatment of invasive aspergillosis, both as frontline and as salvage therapy. Unfortunately, resistance to the triazoles among A. fumigatus isolates is now increasingly reported worldwide, and a large proportion of this resistance remains unexplained. In this work, we characterize the contributions of previously identified mechanisms of triazole resistance, including mutations in the sterol-demethylase-encoding gene cyp51A, overexpression of sterol-demethylase genes, and overexpression of the efflux pump-encoding gene abcC, among a large collection of highly triazole-resistant clinical A. fumigatus isolates. Upon revealing that these mechanisms alone cannot substantiate the majority of triazole resistance exhibited by this collection, we subsequently describe the identification and characterization of a novel genetic determinant of triazole resistance. Mutations in the 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase-encoding gene, hmg1, were identified in a majority of triazole-resistant clinical isolates in our collection. Introduction of three different hmg1 mutations, predicted to encode residue alterations in the conserved sterol sensing domain of Hmg1, resulted in significantly increased resistance to the triazole class of agents. Additionally, correction of a hmg1 mutation in a pan-triazole-resistant clinical isolate of A. fumigatus with a novel Cas9-ribonucleoprotein-mediated system was shown to restore clinical susceptibility to all triazole agents. Mutations in hmg1 were also shown to lead to the accumulation of ergosterol precursors, such as eburicol, by sterol profiling, while not altering the expression of sterol-demethylase genes. IMPORTANCE Aspergillus fumigatus is the predominant pathogen of invasive aspergillosis, a disease state credited with over 200,000 life-threatening infections annually. The triazole class of antifungals are clinically essential to the treatment of invasive aspergillosis. Unfortunately, resistance to the triazoles among A. fumigatus isolates is now increasingly reported worldwide. In this work, we challenge the current paradigm of clinical triazole resistance in A. fumigatus, by first demonstrating that previously characterized mechanisms of resistance have nominal impact on triazole susceptibility and subsequently identifying a novel mechanism of resistance with a profound impact on clinical triazole susceptibility. We demonstrate that mutations in the HMG-CoA reductase gene, hmg1, are common among resistant clinical isolates and that hmg1 mutations confer resistance to all clinically available triazole antifungals.
format	article
author	Jeffrey M. Rybak Wenbo Ge Nathan P. Wiederhold Josie E. Parker Steven L. Kelly P. David Rogers Jarrod R. Fortwendel
author_facet	Jeffrey M. Rybak Wenbo Ge Nathan P. Wiederhold Josie E. Parker Steven L. Kelly P. David Rogers Jarrod R. Fortwendel
author_sort	Jeffrey M. Rybak
title	Mutations in <italic toggle="yes">hmg1</italic>, Challenging the Paradigm of Clinical Triazole Resistance in <named-content content-type="genus-species">Aspergillus fumigatus</named-content>
title_short	Mutations in <italic toggle="yes">hmg1</italic>, Challenging the Paradigm of Clinical Triazole Resistance in <named-content content-type="genus-species">Aspergillus fumigatus</named-content>
title_full	Mutations in <italic toggle="yes">hmg1</italic>, Challenging the Paradigm of Clinical Triazole Resistance in <named-content content-type="genus-species">Aspergillus fumigatus</named-content>
title_fullStr	Mutations in <italic toggle="yes">hmg1</italic>, Challenging the Paradigm of Clinical Triazole Resistance in <named-content content-type="genus-species">Aspergillus fumigatus</named-content>
title_full_unstemmed	Mutations in <italic toggle="yes">hmg1</italic>, Challenging the Paradigm of Clinical Triazole Resistance in <named-content content-type="genus-species">Aspergillus fumigatus</named-content>
title_sort	mutations in <italic toggle="yes">hmg1</italic>, challenging the paradigm of clinical triazole resistance in <named-content content-type="genus-species">aspergillus fumigatus</named-content>
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/1a326c478b58433da1a49105ffc817db
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Mutations in <italic toggle="yes">hmg1</italic>, Challenging the Paradigm of Clinical Triazole Resistance in <named-content content-type="genus-species">Aspergillus fumigatus</named-content>

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