Environmental Triazole Induces Cross-Resistance to Clinical Drugs and Affects Morphophysiology and Virulence of Cryptococcus gattii and C. neoformans

Rafael Wesley Bastos (1) , Hellem Cristina Silva Carneiro (1) , Lorena Vívien Neves Oliveira (1) , Karen Maia Rocha (1) , Gustavo José Cota Freitas (1) , Marliete Carvalho Costa (1) , Thaís Furtado Ferreira Magalhães (1) , Vanessa Silva Dutra Carvalho (1) , Cláudia Emanuela Rocha (2) , Gabriella Freitas Ferreira (3) , Tatiane Alves Paixão (2) , Frederique Moyrand (4) , Guilhem Janbon (4) , Daniel Assis Santos (1)

1 Departamento de Microbiologia, Imunologia e Parasitologia
2 Departamento de Patologia Geral
3 FF - Faculdade de Farmácia [Juiz de Fora, Brazil]
4 Biologie des ARN des Pathogènes fongiques - RNA Biology of Fungal Pathogens

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.

Mots clés: antifungal cross-resistance; fluconazole; pseudohyphae; tebuconazole; agrochemical

Domaines: Mycologie

Rafael Wesley Bastos, Hellem Cristina Silva Carneiro, Lorena Vívien Neves Oliveira, Karen Maia Rocha, Gustavo José Cota Freitas, et al.. Environmental Triazole Induces Cross-Resistance to Clinical Drugs and Affects Morphophysiology and Virulence of Cryptococcus gattii and C. neoformans. Antimicrobial Agents and Chemotherapy, 2018, 62 (1), pp.e01179-17. ⟨10.1128/AAC.01179-17⟩. ⟨pasteur-02652442⟩