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JAC Advance Access published online on November 6, 2009
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkp407
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© The Author 2009. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

Fluconazole at subinhibitory concentrations induces the oxidative- and nitrosative-responsive genes TRR1, GRE2 and YHB1, and enhances the resistance of Candida albicans to phagocytes

David M. Arana, César Nombela and Jesús Pla*

Departamento de Microbiología II, Facultad de Farmacia, Universidad Complutense de Madrid, Plaza de Ramón y Cajal s/n, E-28040 Madrid, Spain

Received 21 July 2009; returned 13 September 2009; revised 25 September 2009; accepted 12 October 2009

* Corresponding author. Tel: +34-91-3941617; Fax: +34-91-3941745; E-mail: jesuspla{at}farm.ucm.es

Objectives: To analyse the oxidative and nitrosative stress response in Candida albicans generated by fluconazole at subinhibitory concentrations, and the functional consequences of such a response for the interaction with phagocytic cells.

Methods: The C. albicans CAI-4 strain carrying transcriptional fusions of the TRR1p, YHB1p and GRE2p genes to the Renilla reniformis luciferase LUC gene was pre-treated with subinhibitory concentrations of fluconazole and incubated with oxidants (diamide and hydrogen peroxide) or with the myelomonocytic cell line HL-60.

Results: Fluconazole induced oxidative and nitrosative stress in a time- and dose-dependent manner as determined using oxidative- and nitrosative-specific gene reporters. At subinhibitory concentrations, fluconazole was able to induce protection in vitro to subsequent challenges with oxidants in both liquid and solid media, and also induced partial protection against the oxidative-mediated killing mechanisms of the myelocytic HL-60 cells.

Conclusions: Subinhibitory concentrations of fluconazole protect against oxidants and killing mediated by phagocytes.

Key Words: C. albicans , adaptation , oxidative stress


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