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Curcumin affects function of Hsp90 and drug efflux pump of Candida albicans
Yean Sheng Lee1, Xinyue Chen1, Tria Widiasih Widiyanto1
1School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Japan.
Abstract:
Candida albicans is a pathogenic yeast that causes candidiasis in immunocompromised patients. The overuse of antifungal drugs has led to the development of resistance to such drugs by this fungus, which is a major challenge in antifungal chemotherapy. One approach to this problem involves the utilization of new natural products as an alternative source of antifungals. Curcumin, one such natural product, has been widely studied as a drug candidate and is reported to exhibit antifungal activity against C. albicans. Although studies of the mechanism of curcumin against human cancer cells have shown that it inhibits heat shock protein 90 (Hsp90), little is known about its function against C. albicans. In this paper, using a doxycycline-mediated HSP90 strain and an HSP90-overexpressing strain of C. albicans, we demonstrated that the curcumin triggered a decrease in Hsp90 by affecting it at the post-transcriptional level. This also led to the downregulation of HOG1 and CDR1, resulting in a reduction of the stress response and efflux pump activity of C. albicans. However, the inhibition of HSP90 by curcumin was not due to the inhibition of transcription factors HSF1 or AHR1. We also found that curcumin can not only decrease the transcriptional expression of CDR1, but also inhibit the efflux pump activity of Cdr1. Hence, we conclude that disruption of HSP90 by curcumin could impair cell growth, stress responses and efflux pump activity of C. albicans.
Insights
Curcumin disrupts heat shock protein 90 (Hsp90) in Candida albicans post-transcriptionally, reducing stress response and drug efflux. This natural compound offers a potential alternative to combat antifungal resistance.
Area of Science:
- Mycology
- Biochemistry
- Antimicrobial Research
Background:
- Antifungal drug resistance in *Candida albicans* is a growing clinical challenge.
- Natural products like curcumin are explored as alternative antifungal agents.
- Curcumin's mechanism against *C. albicans*, particularly its effect on heat shock protein 90 (Hsp90), is not well understood.
Purpose of the Study:
- To investigate the mechanism by which curcumin exerts antifungal activity against *Candida albicans*.
- To determine the role of heat shock protein 90 (Hsp90) in curcumin's antifungal action.
- To elucidate the downstream effects of Hsp90 inhibition by curcumin on fungal stress response and drug resistance.
Main Methods:
- Utilized doxycycline-mediated *HSP90* knockdown and *HSP90*-overexpressing strains of *C. albicans*.
- Analyzed the post-transcriptional effects of curcumin on Hsp90 levels.
- Assessed the impact of curcumin on *HOG1* and *CDR1* gene expression and Cdr1 efflux pump activity.
Main Results:
- Curcumin treatment led to a post-transcriptional decrease in Hsp90 levels in *C. albicans*.
- This Hsp90 reduction resulted in the downregulation of *HOG1* and *CDR1*, impairing stress response and efflux pump activity.
- Curcumin's inhibition of Hsp90 was independent of *HSF1* or *AHR1* transcription factors and directly affected Cdr1 efflux pump function.
Conclusions:
- Curcumin disrupts Hsp90 in *C. albicans* at a post-transcriptional level.
- Inhibition of Hsp90 by curcumin compromises fungal cell growth, stress tolerance, and drug efflux.
- Curcumin presents a promising therapeutic strategy against *Candida albicans* by targeting Hsp90 and overcoming antifungal resistance.
