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Metabonomics on Candida albicans indicate the excessive H3K56ac is involved in the antifungal activity of Shikonin

Version 3 2023-09-20, 05:22
Version 2 2021-09-29, 13:03
Version 1 2019-08-27, 12:10
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posted on 2023-09-20, 05:22 authored by ZeBin Liao, ZhenYu Zhu, Ling Li, Liang Wang, Hui Wang, YuanYing Jiang, YingYing Cao

Development of antifungal agents with novel mechanism and low toxicity are essential due to the prevalence of the infectious diseases caused by Candida albicans. The current study employed a new research method, which combined the ultra-high performance liquid chromatography with quadrupole time-of-flight mass spectrometry and gas chromatography-mass spectrometry, to investigate the intrinsic mechanism of Shikonin (SK) against C. albicans. The levels of 27 metabolites, which mainly involved in histone deacetylation, amino acid synthesis, lipid synthesis, nitrogen metabolism, tricarboxylic acid cycle, oxidative stress and glycolysis, were remarkably changed upon SK treatment. Specially, the down-regulation of nicotinamide (NAM) upon SK treatment indicated the suppression of the deacetylation of the histone H3 on lysine 56 residue (H3K56). Further experiment confirmed that the level of H3K56 acetylation (H3K56ac) was dramatically increased upon SK treatment which was mediated by HST3, the gene encoding the H3K56 deacetylase (Hst3p). Our results demonstrated that SK is the first natural compound reported to execute antifungal activity directly via boosting H3K56ac mediated by HST3. Importantly, this finding shed new light on the mechanisms to relieve the side effects or reverse the drug tolerance, as well as the development of agents for antifungal therapies.

Funding

This work was supported by the 973 Program 2013CB531602 and National Natural Science Foundation of China (81671991 and 81573473) (Ministry of Science and Technology of the People’s Republic of China).

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