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JAC Advance Access originally published online on August 5, 2009
Journal of Antimicrobial Chemotherapy 2009 64(4):764-773; doi:10.1093/jac/dkp273
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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

The alternative oxidase of Candida albicans causes reduced fluconazole susceptibility

Lan Yan1, Miaohai Li2, Yongbing Cao1, Pinghui Gao1, Yingying Cao1, Yan Wang1 and Yuanying Jiang1,*

1 Department of Pharmacology, College of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China 2 Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, People's Republic of China

Received 16 April 2009; returned 4 June 2009; revised 30 June 2009; accepted 5 July 2009

* Corresponding author. Tel: +86-021-8187-1201; Fax: +86-021-6549-0641; E-mail: Jiangyysmmu{at}sina.com

Objectives: To evaluate the effect of Candida albicans mitochondrial respiratory status on antifungal azole susceptibility.

Methods: The inhibitors cyanide and salicylhydroxamic acid (SHAM) were each combined with azoles to examine the effect of the combinations on C. albicans. C. albicans strains deleted for the alternative oxidase (Aox) were also examined for susceptibility to azoles and for the generation of intracellular reactive oxygen species (ROS). A chequerboard microdilution assay was performed on several C. albicans clinical strains including azole-resistant isolates to explore the combined effect of fluconazole and inhibitors of Aox.

Results: The induction of the alternative respiratory pathway by cyanide decreased susceptibility to azoles, while the inhibition of alternative respiration by SHAM increased azole susceptibility. It was found that ROS production was increased in the absence of Aox in C. albicans upon treatment by antifungals such as miconazole and benomyl. The combination of fluconazole with SHAM resulted in a synergistic effect on the killing of C. albicans clinical isolates.

Conclusion: These results demonstrate that the induction of the alternative respiratory pathway confers reduced susceptibility to antifungal azoles, potentially through a mechanism that involves decreased intracellular ROS production during exposure to antifungal agents.

Keywords: drug resistance , alternative pathway , mitochondrion , reactive oxygen species


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