Lanosterol synthase inhibition as a potential approach for re-sensitizing triazole-resistant Aspergillus fumigatus

Xie, Jinhong, Guruceaga, Xabier, Martin-Vicente, Adela, Thorn, Harrison I., Bale, Devi, Cuesta, Uxue Perez, Nandi, Asmita, Dieleman, Chendo, Parker, Josie E., Kelly, Steven L., Müller, Christoph, Gsaller, Fabio and Fortwendel, Jarrod R. 2026. Lanosterol synthase inhibition as a potential approach for re-sensitizing triazole-resistant Aspergillus fumigatus. mBio 17 (8) , e0100226. 10.1128/mbio.01002-26

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Abstract

The increasing prevalence of triazole resistance among Aspergillus fumigatus clinical isolates threatens the efficacy of this front-line treatment, highlighting the urgent need for novel therapeutic targets. In this study, we characterized three putative lanosterol synthase (also known as oxidosqualene cyclase) paralogs and identified Erg7A as the dominant enzyme. Although erg7B provided functional redundancy when overexpressed, deletion of erg7A alone created a significant ergosterol biosynthetic blockade. erg7A deficiency led to the accumulation of upstream substrates (squalene and 2,3-oxidosqualene) as well as downstream sterol intermediates, including lanosterol and eburicol. This sterol perturbation conferred triazole hypersusceptibility to a laboratory strain and restored susceptibility in resistant clinical isolates harboring cyp51A or hmg1 mutations. We further validated these findings using Ro 48-8071, a specific oxidosqualene cyclase inhibitor, and found that Ro 48-8071 exhibited potent synergy with the long-tailed triazoles, itraconazole, and posaconazole. Our findings demonstrate that targeting Erg7 sensitizes A. fumigatus to triazoles, offering a potential combination therapy against resistant isolates.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Schools > Biosciences
Publisher:	American Society for Microbiology
ISSN:	2161-2129
Date of First Compliant Deposit:	30 July 2026
Date of Acceptance:	2 July 2026
Last Modified:	03 Sep 2026 13:38
URI:	https://orca.cardiff.ac.uk/id/eprint/188631

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