Environmental Triazole Induces Cross-Resistance to Clinical Drugs and Affects Morphophysiology and Virulence of Cryptococcus gattii and C. neoformans
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Cryptococcus gattii and Cryptococcus neoformans are environmental fungi that cause cryptococcosis, which is usually treated with amphotericin B and fluconazole. However, therapeutic failure is increasing because of the emergence of resistant strains. Because these species are constantly isolated from vegetal materials and the usage of agrochemicals is growing, we postulate that pesticides could be responsible for the altered susceptibility of these fungi to clinical drugs. Therefore, we evaluated the influence of the pesticide tebuconazole on the susceptibility to clinical drugs, morphophysiology, and virulence of C. gattii and C. neoformans strains. The results showed that tebuconazole exposure caused in vitro cross-resistance (CR) between the agrochemical and clinical azoles (fluconazole, itraconazole, and ravuconazole) but not with amphotericin B. In some strains, CR was observed even after the exposure ceased. Further, tebuconazole exposure changed the morphology, including formation of pseudohyphae in C. neoformans H99, and the surface charge of the cells. Although the virulence of both species previously exposed to tebuconazole was decreased in mice, the tebuconazole-exposed colonies recovered from the lungs were more resistant to azole drugs than the nonexposed cells. This in vivo CR was confirmed when fluconazole was not able to reduce the fungal burden in the lungs of mice. The tolerance to azoles could be due to increased expression of the ERG11 gene in both species and of efflux pump genes ( AFR1 and MDR1 ) in C. neoformans . Our study data support the idea that agrochemical usage can significantly affect human pathogens present in the environment by affecting their resistance to clinical drugs.
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Laboratory studies have shown that selection for resistance to environmental agrochemicals, primarily through upregulation of ERG11 and drug efflux pumps, can lead to cross-resistance to clinically deployed antifungals.
“Laboratory studies have shown that selection for resistance to environmental agrochemicals, primarily through the upregulation of the azole target gene ERG11 and drug efflux pumps, can lead to cross-resistance to clinically deployed antifungals19,20.”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [20]
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- Authors
- Bastos, R. W., Carneiro, H. C. S., Oliveira, L. V. N., Rocha, K. M., Freitas, G. J. C., Costa, M. C., Magalhães, T. F. F., Carvalho, V. S. D., Rocha, C. E., Ferreira, G. F., Paixão, T. A., Moyrand, F., Janbon, G., & Santos, D. A.
- Affiliations
- Universidade Federal de Minas Gerais (BR)
- Universidade Federal de Juiz de Fora (BR)
- Institut Pasteur (FR)
- ORCID
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 2018-01
- Volume
- 62
- Issue
- 1
- Pages
- e01179-17
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC5740350
- OpenAlex
- W2767647365
- Cited by
- 72
- References
- 41
- Citations by year
- 2026: 8 · 2025: 13 · 2024: 4 · 2023: 8 · 2022: 10 · 2021: 8 · 2020: 5 · 2019: 12 · 2018: 4
- FWCI
- 4.50
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Funders
- Fundação de Amparo à Pesquisa do Estado de Minas Gerais - FAPEMIG (APQ-00727-16)
- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES (88881.131683/2016-01)
- MCTI | Conselho Nacional de Desenvolvimento Científico e Tecnológico (403006/2016-3, 305154/2014-1)
- Topics
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Keywords
- Cryptococcus gattii, Cryptococcus neoformans, tebuconazole, triazole fungicides, cross-resistance, azole resistance, amphotericin B susceptibility, fluconazole, itraconazole, ravuconazole, fungal virulence, efflux pumps, MDR1, agrochemical exposure, environmental fungi, cryptococcosis, drug resistance
- MeSH terms
- Animals, Antifungal Agents, Cryptococcosis, Cryptococcus neoformans, Fungicides, Industrial, Male, Mice, Inbred C57BL, Microbial Sensitivity Tests, Triazoles, Virulence, Fluconazole, Drug Resistance, Multiple, Fungal, Cryptococcus gattii
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