Anti-Candida-biofilm activity of micafungin is attenuated by voriconazole but restored by pharmacological inhibition of Hsp90-related stress responses.
We have conducted an in vitro evaluation of the efficacy of a voriconazole-micafungin combination against Candida albicans. When used alone, both micafungin and voriconazole decreased the metabolic activity of planktonic cells, but only micafungin displayed potent anti-biofilm activity. Their combination appeared to have an additive effect against planktonic cells. However, voriconazole significantly antagonized the fungicidal effect of micafungin against Candida biofilms. Time-lag experiments showed that pre-treatment with voriconazole induced resistance to micafungin in Candida biofilms. The micafungin-antagonizing effect of voriconazole persisted even when the biofilm was no longer exposed to voriconazole. In contrast, voriconazole addition after 24 h of micafungin treatment did not alter micafungin sensitivity. To investigate the mechanism of antagonism, we used inhibitors of Hsp90 and its effectors because Hsp90 seems to be implicated in the resistance to micafungin. These molecules reversed the voriconazole-induced resistance to micafungin which suggests that Hsp90-related stress responses are involved in the antagonism. Our results may provide clues as to the mechanism of increased drug resistance in Candida biofilms and raises concerns about the use of the voriconazole-micafungin combination in clinical settings.
Kaneko
Yukihiro
Y
Department of Chemotherapy and Mycosis, National Institute of Infectious Diseases, Tokyo, Japan. ykaneko@nih.go.jp
Ohno
Hideaki
H
Fukazawa
Hidesuke
H
Murakami
Yuko
Y
Imamura
Yoshifumi
Y
Kohno
Shigeru
S
Miyazaki
Yoshitsugu
Y
D000935:Antifungal Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects* / Q000254:growth & development; D019703:Calcineurin / Q000502:physiology; D002176:Candida albicans / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D054714:Echinocandins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000187:drug effects* / Q000502:physiology; D055666:Lipopeptides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000077551:Micafungin; D011743:Pyrimidines / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014230:Triazoles / Q000494:pharmacology*; D065819:Voriconazole
D000935:Antifungal Agents; D054714:Echinocandins; D018841:HSP90 Heat-Shock Proteins; D055666:Lipopeptides; D011743:Pyrimidines; D014230:Triazoles; D019703:Calcineurin; D065819:Voriconazole; D000077551:Micafungin