ArticlePloS one2012
Discovery of a HapE mutation that causes azole resistance in Aspergillus fumigatus through whole genome sequencing and sexual crossing.
Article in PloS one, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 124 papers, 3 of them syntheses that pooled it.
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Who cites it
124 citing papers in PubMed, 3 syntheses or guidelines pooled it, 201 citations in OpenAlex.
- Aspergillus fumigatus-a systematic review to inform the World Health Organization priority list of fungal pathogens.Medical mycology · 2024Pooled it
- The Potential Role of Clinical Metagenomics in Infectious Diseases: Therapeutic Perspectives.Drugs · 2021Pooled it
- Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America.Clinical infectious diseases : an official publication of the Infectious Diseases Society of America · 2016Guideline
- Functional characterization of SHC-like triterpene cyclase genes in azole response and virulence-related traits ofVirulence · 2026Article
- Lanosterol synthase inhibition as a potential approach for re-sensitizing triazole-resistantmBio · 2026Article
- Molecular Mechanisms, Diagnosis, and Therapeutic Strategies of Antifungal Resistance in Filamentous Fungi.Journal of fungi (Basel, Switzerland) · 2026Review
- Genotype-Phenotype Relationships in Azole-ResistantJournal of fungi (Basel, Switzerland) · 2026Review
- Prevalence of cyp51A variants in a US collection of Aspergillus fumigatus clinical isolates and comparative analysis of their contribution to triazole antifungal resistance.The Journal of antimicrobial chemotherapy · 2026Article
- Directed evolution of the pathogenic moldAntimicrobial agents and chemotherapy · 2026Article
- Global epidemiology of azole resistance inJAC-antimicrobial resistance · 2026Review
- Current Evidence on Voriconazole Exposure and Individualized Therapy for Aspergillosis.Infection and drug resistance · 2026Review
- Genomic variant-driven prediction of azole resistance inFrontiers in microbiology · 2026Article
- Azole-ResistantJournal of fungi (Basel, Switzerland) · 2025Review
- RttA, a ZnMicrobiology spectrum · 2025Article
- Genetic analysis of common triazole resistance mechanisms in a collection ofAntimicrobial agents and chemotherapy · 2025Article
- Loss of theMicrobiology spectrum · 2025Article
- Recent developments inMicrobiology and molecular biology reviews : MMBR · 2025Review
- Review
- Detection of pan-azole resistant Aspergillus fumigatus in horticulture and a composting facility in Belgium.Medical mycology · 2024Article
- Azole resistance mechanisms and population structure of the human pathogenApplied and environmental microbiology · 2024Article
64 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
8 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Azole compounds are the primary therapy for patients with diseases caused by Aspergillus fumigatus. However, prolonged treatment may cause resistance to develop, which is associated with treatment failure. The azole target cyp51A is a hotspot for mutations that confer phenotypic resistance, but in an increasing number of resistant isolates the underlying mechanism remains unknown. Here, we report the discovery of a novel resistance mechanism, caused by a mutation in the CCAAT-binding transcription factor complex subunit HapE. From one patient, four A. fumigatus isolates were serially collected. The last two isolates developed an azole resistant phenotype during prolonged azole therapy. Because the resistant isolates contained a wild type cyp51A gene and the isolates were isogenic, the complete genomes of the last susceptible isolate and the first resistant isolate (taken 17 weeks apart) were sequenced using Illumina technology to identify the resistance conferring mutation. By comparing the genome sequences to each other as well as to two A. fumigatus reference genomes, several potential non-synonymous mutations in protein-coding regions were identified, six of which could be confirmed by PCR and Sanger sequencing. Subsequent sexual crossing experiments showed that resistant progeny always contained a P88L substitution in HapE, while the presence of the other five mutations did not correlate with resistance in the progeny. Cloning the mutated hapE gene into the azole susceptible akuB(KU80) strain showed that the HapE P88L mutation by itself could confer the resistant phenotype. This is the first time that whole genome sequencing and sexual crossing strategies have been used to find the genetic basis of a trait of interest in A. fumigatus. The discovery may help understand alternate pathways for azole resistance in A. fumigatus with implications for the molecular diagnosis of resistance and drug discovery.
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