Abstract
Recently, mutations in the 3-hydroxy-3-methylglutaryl-coenzyme-A-reductase-encoding gene (hmg1), a gene involved in ergosterol production, were associated with triazole-resistance in Aspergillus fumigatus. In this study, we determined the prevalence and characteristics of hmg1 mutations in a collection of clinical triazole-resistant A. fumigatus isolates collected during 2001–2019 from two international mycology reference centers: the Belgian National Reference Center for Mycosis and the Center of Expertise in Mycology Radboudumc/CWZ. Clinical isolates with and without cyp51A gene mutations and randomly selected wild-type (WT) controls were included. Isolates were characterized by in vitro susceptibility testing, cyp51A and hmg1 sequencing, and short tandem repeat typing. Available clinical records were analyzed for previous triazole exposure. In 23 isolates (24%) of the 95 triazole-resistant A. fumigatus isolates, hmg1 gene mutations were observed; including 5/23 (22%) isolates without cyp51A gene mutations and 18/72 (25%) with cyp51A mutations. Four previously described hmg1 gene mutations (E105K, G307R/D, G466V, and S541G) and two novel mutations (W273S and L304P) were found; 4/23 (17%) in the sterol-sensing-domain region. No triazole-antifungal exposure was reported in 75% (9/12) of patients harboring an isolate with hmg1 gene mutations. Three of 39 WT isolates (8%) contained a hmg1 gene mutation; E105K (2-isolates) and S541G. Hmg1 gene mutations were predominantly found in A. fumigatus with cyp51A mutations with voriconazole MICs ≥ 8 mg/L.
Highlights
The triazole antifungal agents are recommended for prophylaxis and first-line treatment of Aspergillus related-diseases [1,2]
Triazole-resistance screening of A. fumigatus isolates followed by susceptibility determination (EUCAST broth microdilution reference method) of suspected triazole-resistant isolates were performed as previously described [16]
We report a prevalence of 24% hmg1 gene mutations (23/95) in general and of 4.2% in the sensing domain region (SSD)
Summary
The triazole antifungal agents are recommended for prophylaxis (posaconazole) and first-line treatment (voriconazole and isavuconazole) of Aspergillus related-diseases [1,2]. Triazole antifungals enter the active site of the Cyp51A enzyme (sterol-demethylase) blocking the access of lanosterol and its conversion to ergosterol This leads the accumulation of toxic sterol intermediates and ergosterol depletion causing fungal cell growth inhibition and death [5]. A. fumigatus strain, resulted in reduction of triazole susceptibility and accumulation of ergosterol precursors without modifying cyp51A gene expression [9]. Replacement of these substitutions to WT hmg restored susceptibility, relating these mutations to triazole-resistance. As observed by Hagiwara et al, mutations in this region may impair the inhibitory signals that initiate the degradation of Hmg leading to ergosterol accumulation and increasing the amount of triazole antifungal required to inhibit fungal growth [8]. We determined the prevalence of mutations in the hmg gene in a large collection of triazole-resistant A. fumigatus isolates with and without cyp51A gene mutations from two international mycology reference centers
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
