Metabonomics on <i>Candida albicans</i> indicate the excessive H3K56ac is involved in the antifungal activity of Shikonin

Development of antifungal agents with novel mechanism and low toxicity are essential due to the prevalence of the infectious diseases caused by <i>Candida albicans</i>. 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 <i>C. albicans</i>. 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 <i>HST3</i>, 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 <i>HST3</i>. 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.