The alternative oxidase of Candida albicans causes reduced fluconazole susceptibility.
OBJECTIVE
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.


CONCLUSIONS
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.
Yan
Lan
L
Department of Pharmacology, College of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China.
Li
Miaohai
M
Cao
Yongbing
Y
Gao
Pinghui
P
Cao
Yingying
Y
Wang
Yan
Y
Jiang
Yuanying
Y
D000935:Antifungal Agents / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D003486:Cyanides / Q000494:pharmacology; D020536:Enzyme Activators / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015725:Fluconazole / Q000494:pharmacology*; D017353:Gene Deletion; D008826:Microbial Sensitivity Tests; D024101:Mitochondrial Proteins; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D010940:Plant Proteins; D012457:Salicylamides / Q000494:pharmacology; D000099188:Alternative Oxidase
D000935:Antifungal Agents; D003486:Cyanides; D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D015725:Fluconazole; D024101:Mitochondrial Proteins; D010088:Oxidoreductases; D010940:Plant Proteins; D012457:Salicylamides; D000099188:Alternative Oxidase; C005703:salicylhydroxamic acid