Histone acetyltransferase Rtt109 is required for Candida albicans pathogenesis.
Acetylation of histone H3 lysine 56 (H3K56) by the fungal-specific histone acetyltransferase Rtt109 is important for yeast model organisms to survive DNA damage and maintain genome integrity
We conclude that Rtt109 is particularly important for fungal pathogenicity, suggesting a unique target for therapeutic antifungal compounds
Antifungal drugs: Targeting histone acetylation.
Sodium butyrate inhibits pathogenic yeast growth and enhances the functions of macrophages.
Butyrate is a short-chain fatty acid that is produced by several human commensal bacteria, such as Clostridium and Lactobacillus species. Butyrate is also known to inhibit histone deacetylase. In this study we assessed the antifungal activity of sodium butyrate (SB) against the human pathogenic yeasts Candida albicans, Candida parapsilosis and Cryptococcus neoformans.
These results demonstrate that SB exerts significant antifungal activity on pathogenic yeasts and enhances the antimicrobial actions of macrophages in response to these microbes.
Discovery of uracil-based histone deacetylase inhibitors able to reduce acquired antifungal resistance and trailing growth in Candida albicans.
Among fungal pathogens such as Candida albicans, acquired drug resistance has not been associated with plasmids or other transferable elements, but it is thought to involve primarily mutations and genetic or epigenetic phenomena. This prompted us to test some histone deacetylase inhibitors (HDACi) from our library, in combination with fluconazole, against C. albicans strains in vitro. Among the tested compounds, the two chloro-containing uracil-hydroxamates 1c and 1d showed a strong reduction of the MIC values on Candida strains that show the trailing growth effect. In this assay, 1c,d were more potent than SAHA, a well-known HDAC inhibitor, in reducing the Candida growth. More interestingly, 1c,d as well as SAHA were able to inhibit the fluconazole-induced resistance induction in Candida cultures.
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Modulation of histone H3 lysine 56 acetylation as an antifungal therapeutic strategy.
Here we demonstrate that H3K56ac in C. albicans is regulated by the RTT109 and HST3 genes, which respectively encode the H3K56 acetyltransferase (Rtt109p) and deacetylase (Hst3p). We show that reduced levels of H3K56ac sensitize C. albicans to genotoxic and antifungal agents. Inhibition of Hst3p activity by conditional gene repression or nicotinamide treatment results in a loss of cell viability associated with abnormal filamentous growth, histone degradation and gross aberrations in DNA staining.
Nicotinamide inhibits growth of several clinically important pathogenic fungi. :
Modulation of Morphogenesis in Candida albicans by Various Small Molecules [down-pointing small open triangle]
The yeast-to-hypha transition contributes to the overall virulence of C. albicans and may even constitute a target for the development of antifungal drugs. Indeed, impairing morphogenesis in C. albicans has been shown to be a means to treat candidiasis. Additionally, a large number of small molecules such as farnesol, fatty acids, rapamycin, geldanamycin, histone deacetylase inhibitors, and cell cycle inhibitors have been reported to modulate the yeast-to-hypha transition in C. albicans.
The pharmacological inhibition of Hst3p using nicotinamide or the genetic depletion ofHST3 not only induced filamentation but also attenuated virulence in a model of systemic candidiasis. Yet, reduced virulence in vivo was likely due to reduced growth rates rather than to the modulation of morphology, as nicotinamide treatment or the repression of HST3 resulted in cell death.
On the basis of current findings, it appears that modulating morphogenesis is a means to treat mucosal/superficial Candida infections. As for systemic candidiasis, the lack of literature renders it difficult to reach similar conclusions. To circumvent this impediment, small molecules that modulate the Y-H transition in C. albicanswithout affecting cellular growth should be evaluated for their therapeutic potential in various infection models. More data are needed to determine whether or not targeting the Y-H transition constitutes a sound therapeutic strategy to treat Candidainfections.
Activity of MGCD290, a Hos2 histone deacetylase inhibitor, in combination with azole antifungals against opportunistic fungal pathogens.
Thus, MGCD290 demonstrated in vitro synergy with azoles against the majority of clinical isolates tested, including many azole-resistant isolates and genera inherently resistant to azoles (e.g., Mucor and Fusarium). Further evaluation of fungal HDAC inhibitor-azole combinations is indicated.
Inhibitory effect of nicotinamide on enzymatic activity of selected fungal strains causing skin infection
Pathogenicity of fungi is connected with their ability to easily penetrate the host tissues, survive in the infected host organism and use the elements of the host tissues as nutrients. Hence, the co-occurrence of pathogenic properties with the high enzymatic activity, which is manifested through the production of various enzymes including extracellular enzymes, was observed. It can be expected that it is possible to decrease fungal pathogenicity by lowering their enzymatic activity. The aim of the study was to determine the effect of nicotinamide on enzymatic activity of the fungi, which are most frequently isolated in cases of skin infection. Enzymatic activity was analysed using 15 Candida albicans, 15 Trichophyton rubrum and 15 Trichophyton mentagrophytes strains. The strains used for the study were collected from the current diagnostic material. API ZYM tests were used in diagnostic analysis. MICs of nicotinamide were determined by the macrodilution method in liquid medium. In the case of Candida strains, the presence of nicotinamide in the broth had a significant effect on the decrease of enzymatic activity (P < 0.05) of esterase (C4), esterase lipase (C-8), valin-arylamidase, acid phosphatase and alpha-glycosydase. A considerably stronger effect of nicotinamide was observed in the case of dermatophytes (P < 0.005). Its action led to a decrease in the activity of all the enzymes under study except alpha-glucosidase produced by T. rubrum strains. Thus, nicotinamide exhibited biological activity towards C. albicans, T. rubrum and Trichophyton mentagrophytes, which resulted in a decrease in the activity of enzymes produced by the fungi.