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Life sciences

IF: 5.2
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Geldanamycin confers fungicidal properties to azole by triggering the activation of succinate dehydrogenase

Published:6 May 2024 DOI: 10.1016/j.lfs.2024.122699 PMID: 38718854
Juan Xiong, Li Wang, Yanru Feng, Cheng Zhen, Sijin Hang, Jinhua Yu, Hui Lu, Yuanying Jiang

Abstract

Aims

Azoles have been widely employed for the treatment of invasive fungal diseases; however, their efficacy is diminished as pathogenic fungi tolerate them due to their fungistatic properties. Geldanamycin (GdA) can render azoles fungicidal by inhibiting the ATPase and molecular chaperone activities of heat shock protein 90 (Hsp90). Nonetheless, the clinical applicability of GdA is restricted due to its cytotoxic ansamycin scaffold structure, its induction of cytoprotective heat shock responses, and the conservative nature of Hsp90. Hence, it is imperative to elucidate the mechanism of action of GdA to confer fungicidal properties to azoles and mitigate the toxic adverse effects associated with GdA.

Materials and methods

Through various experimental methods, including the construction of gene-deleted Candida albicans mutants, in vitro drug sensitivity experiments, Western blot analysis, reactive oxygen species (ROS) assays, and succinate dehydrogenase activity assays, we identified Hsp90 client proteins associated with the tolerance of C. albicans to azoles.

Key findings

It was observed that GdA effectively hindered the entry of Hsp90 into mitochondria, resulting in the alleviation of inhibitory effect of Hsp90 on succinate dehydrogenase. Consequently, the activation of succinate dehydrogenase led to an increased production of ROS. within the mitochondria, thereby facilitating the antifungal effects of azoles against C. albicans.

Significance

This research presents a novel approach for conferring fungicidal properties to azoles, which involves specifically disrupting the interaction of between Hsp90 and succinate dehydrogenase rather than employing a non-specific inhibition of ATPase activity of Hsp90.

Substances (24)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Bortezomib 179324-69-7 C19H25BN4O4 850 suppliers $10.00-$2516.45
Bortezomib 179324-69-7 C19H25BN4O4 850 suppliers $10.00-$2516.45
Bortezomib 179324-69-7 C19H25BN4O4 850 suppliers $10.00-$2516.45
Bortezomib 179324-69-7 C19H25BN4O4 850 suppliers $10.00-$2516.45
Geldanamycin 30562-34-6 C29H40N2O9 374 suppliers $14.00-$3791.00
Geldanamycin 30562-34-6 C29H40N2O9 374 suppliers $14.00-$3791.00
Geldanamycin 30562-34-6 C29H40N2O9 374 suppliers $14.00-$3791.00
Geldanamycin 30562-34-6 C29H40N2O9 374 suppliers $14.00-$3791.00
17-AAG 75747-14-7 C31H43N3O8 291 suppliers $18.00-$8100.00
17-AAG 75747-14-7 C31H43N3O8 291 suppliers $18.00-$8100.00

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