The effects of an hsp90 inhibitor on the paradoxical effect.
It is important to conserve the effectiveness of antifungal agents because the options for currently available agents are limited. Although echinocandins, which have been developed in recent decades, are highly active against a broad spectrum of fungi, one concern is their reduced activity against Candida albicans at high drug concentrations, which is known as the paradoxical effect. To date, resistance related to the paradoxical effect has not been reported in clinical situations, but some in vivo data suggest that the paradoxical effect potentiates the emergence of resistance. It is valuable to investigate the underlying mechanisms of as well as strategies against this paradoxical resistance. Previous reports imply that the paradoxical effect might be related to stress responses. In this study, we report that radicicol, a heat shock protein 90 (Hsp90) inhibitor, reduces the paradoxical effect of micafungin. We also confirm that radicicol reduces the tolerance to voriconazole, one of the new azoles, which is consistent with a previous report. Our results may therefore imply that common stress responses might exist in the paradoxical resistance to micafungin and also the tolerance to voriconazole, and may suggest that inhibiting Hsp90-related stress responses could help to avoid potential resistances.
Kaneko
Yukihiro
Y
Department of Chemotherapy and Mycoses, National Institute of Infectious Diseases, Tokyo 162-8640, Japan. ykaneko@nih.go.jp
Ohno
Hideaki
H
Imamura
Yoshifumi
Y
Kohno
Shigeru
S
Miyazaki
Yoshitsugu
Y
D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects*; D054714:Echinocandins / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005658:Fungi; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D055666:Lipopeptides / Q000494:pharmacology*; D018942:Macrolides / Q000494:pharmacology*; D000077551:Micafungin; D008826:Microbial Sensitivity Tests; D011743:Pyrimidines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D065819:Voriconazole
D000935:Antifungal Agents; D054714:Echinocandins; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D055666:Lipopeptides; D018942:Macrolides; D011743:Pyrimidines; D014230:Triazoles; C035359:monorden; D065819:Voriconazole; D000077551:Micafungin