{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:17:13Z","timestamp":1790741833385,"version":"4.1.0"},"reference-count":40,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2024,9,20]],"date-time":"2024-09-20T00:00:00Z","timestamp":1726790400000},"content-version":"vor","delay-in-days":19,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Mycoses"],"published-print":{"date-parts":[[2024,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Terbinafine is widely used to treat onychomycosis caused by dermatophyte fungi. Terbinafine resistance in recent years is causing concern. Resistance has so far been associated with single\u2010nucleotide substitutions in the DNA sequence of the enzyme squalene epoxidase (SQLE) but how this affects SQLE functionality is not understood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objectives<\/jats:title><jats:p>The aim of this study was to understand newly discovered resistance in two Australian strains of <jats:italic>Trichophyton interdigitale<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Patients\/Methods<\/jats:title><jats:p>Resistance to terbinafine was tested in four newly isolated strains. Three\u2010dimensional SQLE models were prepared to investigate how the structure of their SQLE affected the binding of terbinafine.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>This study found the first Australian occurrences of terbinafine resistance in two <jats:italic>T. interdigitale<\/jats:italic> strains. Both strains had novel deletion mutations in <jats:italic>erg<\/jats:italic>1 and frameshifts during translation. Three\u2010dimensional models had smaller SQLE proteins and open reading frames as well as fewer C\u2010terminal \u03b1\u2010helices than susceptible strains. In susceptible strains, the lipophilic tail of terbinafine was predicted to dock stably into a hydrophobic pocket in SQLE lined by over 20 hydrophobic amino acids. In resistant strains, molecular dynamics simulations showed that terbinafine docking was unstable and so terbinafine did not block squalene metabolism and ultimately ergosterol production. The resistant reference strain ATCC MYA\u20104438 <jats:italic>T. rubrum<\/jats:italic> showed a single <jats:italic>erg<\/jats:italic>1 mutation that resulted in frameshift during translation, leading to C\u2010terminal helix deletion.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Modelling their effects on their SQLE proteins will aid in the design of potential new treatments for these novel resistant strains, which pose clinical problems in treating dermatophyte infections with terbinafine.<\/jats:p><\/jats:sec>","DOI":"10.1111\/myc.13795","type":"journal-article","created":{"date-parts":[[2024,9,21]],"date-time":"2024-09-21T03:40:15Z","timestamp":1726890015000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["New Sources of Resistance to Terbinafine Revealed and Squalene Epoxidase Modelled in the Dermatophyte Fungus <i>Trichophyton interdigitale<\/i> From 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