ArticleAntimicrobial agents and chemotherapy2015
Heteroresistance to Itraconazole Alters the Morphology and Increases the Virulence of Cryptococcus gattii.
Article in Antimicrobial agents and chemotherapy, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 40 citations in OpenAlex.
- Beyond antifungal susceptibility: molecular mechanisms, detection, and clinical implications of fungal heteroresistance.Molecular biology reports · 2026Review
- Article
- Investigation of voriconazole heteroresistance in clinical isolates ofMicrobiology spectrum · 2025Article
- Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance.Journal of fungi (Basel, Switzerland) · 2025Review
- Influence of the agrochemical benomyl on Cryptococcus gattii-plant interaction in vitro and in vivo.Brazilian journal of microbiology : [publication of the Brazilian Society for Microbiology] · 2024Article
- Pathogenic potential of an environmental Aspergillus fumigatus strain recovered from soil of Pygoscelis papua (Gentoo penguins) colony in Antarctica.Brazilian journal of microbiology : [publication of the Brazilian Society for Microbiology] · 2024Article
- The Dynamics ofCells · 2022Article
- Early clinical and microbiological predictors of outcome in hospitalized patients with cryptococcal meningitis.BMC infectious diseases · 2022Article
- Fungicide effects on human fungal pathogens: Cross-resistance to medical drugs and beyond.PLoS pathogens · 2021Review
- Heteroresistance: A cause of unexplained antibiotic treatment failure?PLoS pathogens · 2019Review
- Cryptococcosis due toMedical mycology case reports · 2019Article
- Evaluation of the interaction between polymyxin B and Pseudomonas aeruginosa biofilm and planktonic cells: reactive oxygen species induction and zeta potential.BMC microbiology · 2019Article
- Evaluation ofFrontiers in microbiology · 2019Article
- A phenylthiazole derivative demonstrates efficacy on treatment of the cryptococcosis & candidiasis in animal models.Future science OA · 2018Article
- Article
- Environmental Triazole Induces Cross-Resistance to Clinical Drugs and Affects Morphophysiology and Virulence of Cryptococcus gattii and C. neoformans.Antimicrobial agents and chemotherapy · 2018Article
- The status of cryptococcosis in Latin America.Memorias do Instituto Oswaldo Cruz · 2018Review
- Ecoepidemiology of Cryptococcus gattii in Developing Countries.Journal of fungi (Basel, Switzerland) · 2017Review
- High-dose fluconazole in combination with amphotericin B is more efficient than monotherapy in murine model of cryptococcosis.Scientific reports · 2017Article
- Eugenol Induces Phenotypic Alterations and Increases the Oxidative Burst inFrontiers in microbiology · 2017Article
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Cryptococcus gattii is the main etiological agent of cryptococcosis in immunocompetent individuals. The triazole drug itraconazole is one of the antifungals used to treat patients with cryptococcosis. Heteroresistance is an adaptive mechanism to counteract the stress of increasing drug concentrations, and it can enhance the ability of a microorganism to survive under antifungal pressure. In this study, we evaluated the ability of 11 C. gattii strains to develop itraconazole heteroresistance. Heteroresistant clones were analyzed for drug susceptibility, alterations in cell diameter, capsule properties, and virulence in a murine model. Heteroresistance to itraconazole was intrinsic in all of the strains analyzed, reduced both the capsule size and the cell diameter, induced molecular heterogeneity at the chromosomal level, changed the negatively charged cells, reduced ergosterol content, and improved the antioxidant system. A positive correlation between surface/volume ratio of original cells and the level of heteroresistance to itraconazole (LHI) was observed in addition to a negative correlation between capsule size of heteroresistant clones and LHI. Moreover, heteroresistance to itraconazole increased the engulfment of C. gattii by macrophages and augmented fungal proliferation inside these cells, which probably accounted for the reduced survival of the mice infected with the heteroresistant clones and the higher fungal burden in lungs and brain. Our results indicate that heteroresistance to itraconazole is intrinsic and increases the virulence of C. gattii. This phenomenon may represent an additional mechanism that contributes to relapses of cryptococcosis in patients during itraconazole therapy.
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