Hmg1 Gene Mutation Prevalence in Triazole-Resistant Aspergillus fumigatus Clinical Isolates
by
Agustin Resendiz-Sharpe 1
, Margriet W.J. Hokken 2, Toine Mercier 1,3, Rita Merckx 1, Kamiel Verhagen 2, Lisa Dewitte 1, Willem J.G. Melchers 2,4, Paul E. Verweij 2,4, Johan Maertens 1,3 and 
Katrien Lagrou 1,5,*
Agustin Resendiz-Sharpe 1, Margriet W.J. Hokken 2, Toine Mercier 1,3, Rita Merckx 1, Kamiel Verhagen 2, Lisa Dewitte 1, Willem J.G. Melchers 2,4, Paul E. Verweij 2,4, Johan Maertens 1,3 and Katrien Lagrou 1,5,*
1
Department of Microbiology, Immunology and Transplantation, Laboratory of Clinical Bacteriology and Mycology, KU Leuven, 3000 Leuven, Belgium
2
Department of Medical Microbiology, Radboud University Nijmegen Medical Center, Radboud Institute for Molecular Life Sciences, 6525 Nijmegen, The Netherlands
3
Department of Hematology, University Hospitals Leuven, 3000 Leuven, Belgium
4
Center of Expertise in Mycology, Radboudumc/CWZ, 6525 Nijmegen, The Netherlands
5
Department of Laboratory Medicine and National Reference Center for Mycosis, Excellence Center for Medical Mycology (ECMM), University Hospitals Leuven, 3000 Leuven, Belgium
*
Author to whom correspondence should be addressed.
J. Fungi 2020, 6(4), 227; https://doi.org/10.3390/jof6040227
Received: 1 September 2020 / Revised: 2 October 2020 / Accepted: 14 October 2020 / Published: 16 October 2020
(This article belongs to the Special Issue Interplay between Antifungal Resistance and Virulence: Potential Novel Targets and Therapeutic Strategies)
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.
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Keywords:
Aspergillus fumigatus; triazole-resistance; hmg1 gene
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MDPI and ACS Style
Resendiz-Sharpe, A.; Hokken, M.W.; Mercier, T.; Merckx, R.; Verhagen, K.; Dewitte, L.; Melchers, W.J.; Verweij, P.E.; Maertens, J.; Lagrou, K. Hmg1 Gene Mutation Prevalence in Triazole-Resistant Aspergillus fumigatus Clinical Isolates. J. Fungi 2020, 6, 227.
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