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Open AccessArticle

Insights into the Multi-Azole Resistance Profile in Candida haemulonii Species Complex

1
Laboratório de Estudos Avançados de Microrganismos Emergentes e Resistentes (LEAMER), Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de Góes (IMPG), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-901, Brazil
2
Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul 91540-000, Brazil
3
Programa de Pós-Graduação em Bioquímica (PPGBq), Instituto de Química (IQ), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-909, Brazil
*
Author to whom correspondence should be addressed.
J. Fungi 2020, 6(4), 215; https://doi.org/10.3390/jof6040215
Received: 15 September 2020 / Revised: 6 October 2020 / Accepted: 8 October 2020 / Published: 11 October 2020
(This article belongs to the Special Issue Systemic and Emerging Mycoses)
The Candida haemulonii complex (C. duobushaemulonii, C. haemulonii, and C. haemulonii var. vulnera) is composed of emerging, opportunistic human fungal pathogens able to cause invasive infections with high rates of clinical treatment failure. This fungal complex typically demonstrates resistance to first-line antifungals, including fluconazole. In the present work, we have investigated the azole resistance mechanisms expressed in Brazilian clinical isolates forming the C. haemulonii complex. Initially, 12 isolates were subjected to an antifungal susceptibility test, and azole cross-resistance was detected in almost all isolates (91.7%). In order to understand the azole resistance mechanistic basis, the efflux pump activity was assessed by rhodamine-6G. The C. haemulonii complex exhibited a significantly higher rhodamine-6G efflux than the other non-albicans Candida species tested (C. tropicalis, C. krusei, and C. lusitaneae). Notably, the efflux pump inhibitors (Phe-Arg and FK506) reversed the fluconazole and voricolazole resistance phenotypes in the C. haemulonii species complex. Expression analysis indicated that the efflux pump (ChCDR1, ChCDR2, and ChMDR1) and ERG11 genes were not modulated by either fluconazole or voriconazole treatments. Further, ERG11 gene sequencing revealed several mutations, some of which culminated in amino acid polymorphisms, as previously reported in azole-resistant Candida spp. Collectively, these data point out the relevance of drug efflux pumps in mediating azole resistance in the C. haemulonii complex, and mutations in ERG11p may contribute to this resistance profile. View Full-Text
Keywords: azole resistance; efflux pumps; fluconazole; lanosterol 14α-demethylase; non-albicans Candida species; voriconazole azole resistance; efflux pumps; fluconazole; lanosterol 14α-demethylase; non-albicans Candida species; voriconazole
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Silva, L.N.; Ramos, L.S.; Oliveira, S.S.C.; Magalhães, L.B.; Squizani, E.D.; Kmetzsch, L.; Vainstein, M.H.; Branquinha, M.H.; Santos, A.L.S. Insights into the Multi-Azole Resistance Profile in Candida haemulonii Species Complex. J. Fungi 2020, 6, 215.

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