Hmg1 Gene Mutation Prevalence in Triazole-Resistant Aspergillus fumigatus Clinical Isolates
Open Access
- 15 October 2020
- journal article
- research article
- Published by MDPI AG in Journal of Fungi
- Vol. 6 (4), 227
- https://doi.org/10.3390/jof6040227
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.This publication has 24 references indexed in Scilit:
- Association Between Initial Route of Fluoroquinolone Administration and Outcomes in Patients Hospitalized for Community-acquired PneumoniaClinical Infectious Diseases, 2016
- Genotype–phenotype complexity of the TR46/Y121F/T289A cyp51A azole resistance mechanism in Aspergillus fumigatusFungal Genetics and Biology, 2015
- Nationwide Surveillance of Azole Resistance in Aspergillus DiseasesAntimicrobial Agents and Chemotherapy, 2015
- The cdr1B efflux transporter is associated with non-cyp51a-mediated itraconazole resistance in Aspergillus fumigatusJournal of Antimicrobial Chemotherapy, 2013
- The structure–function relationship of the Aspergillus fumigatuscyp51A L98H conversion by site-directed mutagenesis: The mechanism of L98H azole resistanceFungal Genetics and Biology, 2011
- The Sterol-sensing Domain (SSD) Directly Mediates Signal-regulated Endoplasmic Reticulum-associated Degradation (ERAD) of 3-Hydroxy-3-methylglutaryl (HMG)-CoA Reductase Isozyme Hmg2Online Journal of Public Health Informatics, 2011
- Azole Resistance Profile of Amino Acid Changes in Aspergillus fumigatus CYP51A Based on Protein Homology ModelingAntimicrobial Agents and Chemotherapy, 2010
- Emergence of Azole Resistance in Aspergillus fumigatus and Spread of a Single Resistance MechanismPLoS Medicine, 2008
- Use of a Novel Panel of Nine Short Tandem Repeats for Exact and High-Resolution Fingerprinting of Aspergillus fumigatus IsolatesJournal of Clinical Microbiology, 2005
- Membrane-bound domain of HMG CoA reductase is required for sterol-enhanced degradation of the enzymeCell, 1985