Mutations in hmg1, challenging the paradigm of clinical triazole resistance in Aspergillus fumigatus

Rybak, Jeffrey M., Ge, Wenbo, Wiederhold, Nathan P., Parker, Josie E., Kelly, Steven L., Rogers, P. David, Fortwendel, Jarrod R. and Alspaugh, J. Andrew 2019. Mutations in hmg1, challenging the paradigm of clinical triazole resistance in Aspergillus fumigatus. mBio 10 (2) , e00437-19. 10.1128/mBio.00437-19

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Publisher:	American Society for Microbiology
ISSN:	2161-2129
Date of First Compliant Deposit:	8 July 2022
Date of Acceptance:	20 February 2019
Last Modified:	12 May 2023 17:37
URI:	https://orca.cardiff.ac.uk/id/eprint/151164

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