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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Candida parapsilosis Resistance to Fluconazole: Molecular Mechanisms and In Vivo Impact in Infected Galleria mellonella Larvae

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Author(s):
Souza, Ana Carolina R. [1] ; Fuchs, Beth Burgwyn [2] ; Pinhati, Henrique M. S. [3, 4] ; Siqueira, Ricardo A. [1] ; Hagen, Ferry [5] ; Meis, Jacques F. [5, 6] ; Mylonakis, Eleftherios [2] ; Colombo, Arnaldo L. [1]
Total Authors: 8
Affiliation:
[1] Univ Fed Sao Paulo, Escola Paulista Med, Disciplina Infectol, Lab Especial Micol, Sao Paulo, SP - Brazil
[2] Brown Univ, Rhode Isl Hosp, Alpert Med Sch, Div Infect Dis, Providence, RI 02903 - USA
[3] Univ Brasilia, Brasilia, DF - Brazil
[4] Hosp Santa Luzia, Brasilia, DF - Brazil
[5] Canisius Wilhelmina Hosp, Dept Med Microbiol & Infect Dis, Nijmegen - Netherlands
[6] Radboud Univ Nijmegen, Med Ctr, Dept Med Microbiol, NL-6525 ED Nijmegen - Netherlands
Total Affiliations: 6
Document type: Journal article
Source: Antimicrobial Agents and Chemotherapy; v. 59, n. 10, p. 6581-6587, OCT 2015.
Web of Science Citations: 36
Abstract

Candida parapsilosis is the main non-albicans Candida species isolated from patients in Latin America. Mutations in the ERG11 gene and overexpression of membrane transporter proteins have been linked to fluconazole resistance. The aim of this study was to evaluate the molecular mechanisms in fluconazole-resistant strains of C. parapsilosis isolated from critically ill patients. The identities of the nine collected C. parapsilosis isolates at the species level were confirmed through molecular identification with a TaqMan qPCR assay. The clonal origin of the strains was checked by microsatellite typing. The Galleria mellonella infection model was used to confirm in vitro resistance. We assessed the presence of ERG11 mutations, as well as the expression of ERG11 and two additional genes that contribute to antifungal resistance (CDR1 and MDR1), by using real-time quantitative PCR. All of the C. parapsilosis (sensu stricto) isolates tested exhibited fluconazole MICs between 8 and 16 mu g/ml. The in vitro data were confirmed by the failure of fluconazole in the treatment of G. mellonella infected with fluconazole-resistant strains of C. parapsilosis. Sequencing of the ERG11 gene revealed a common mutation leading to a Y132F amino acid substitution in all of the isolates, a finding consistent with their clonal origin. After fluconazole exposure, overexpression was noted for ERG11, CDR1, and MDR1 in 9/9, 9/9, and 2/9 strains, respectively. We demonstrated that a combination of molecular mechanisms, including the presence of point mutations in the ERG11 gene, overexpression of ERG11, and genes encoding efflux pumps, are involved in fluconazole resistance in C. parapsilosis. (AU)

FAPESP's process: 12/04769-4 - Candida parapsilosis complex: epidemiological peculiarities, virulence and mechanisms of antifungal resistance
Grantee:Ana Carolina Remondi Souza
Support Opportunities: Scholarships in Brazil - Doctorate
FAPESP's process: 12/04767-1 - Candida parapsilosis complex: epidemiological peculiarities, virulence and mechanisms of antifungal resistance
Grantee:Arnaldo Lopes Colombo
Support Opportunities: Regular Research Grants
FAPESP's process: 13/07405-6 - Pathogenicity analysis of C. parapsilosis species complex in experimental models of invertebrates
Grantee:Ana Carolina Remondi Souza
Support Opportunities: Scholarships abroad - Research Internship - Doctorate