Histone Deacetylases and Their Inhibition in Candida Species.

Cécile Garnaud,Morgane Champleboux,Muriel Cornet,Danièle Maubon,Jérôme Govin

doi:10.3389/fmicb.2016.01238

Abstract

Fungi are generally benign members of the human mucosal flora or live as saprophytes in the environment. However, they can become pathogenic, leading to invasive and life threatening infections in vulnerable patients. These invasive fungal infections are regarded as a major public health problem on a similar scale to tuberculosis or malaria. Current treatment for these infections is based on only four available drug classes. This limited therapeutic arsenal and the emergence of drug-resistant strains are a matter of concern due to the growing number of patients to be treated, and new therapeutic strategies are urgently needed. Adaptation of fungi to drug pressure involves transcriptional regulation, in which chromatin dynamics and histone modifications play a major role. Histone deacetylases (HDACs) remove acetyl groups from histones and actively participate in controlling stress responses. HDAC inhibition has been shown to limit fungal development, virulence, biofilm formation, and dissemination in the infected host, while also improving the efficacy of existing antifungal drugs toward Candida spp. In this article, we review the functional roles of HDACs and the biological effects of HDAC inhibitors on Candida spp., highlighting the correlations between their pathogenic effects in vitro and in vivo. We focus on how HDAC inhibitors could be used to treat invasive candidiasis while also reviewing recent developments in their clinical evaluation.

Highlights

Reviewed by: Nir Osherov, Tel Aviv University, Israel Dimitrios P
MGCD290 potentiates the activity of triazoles against Candida spp. in vitro (Pfaller et al, 2009, 2015). This synergy between Histone deacetylases (HDACs) inhibitors and antifungals is not limited to azoles, and Trichostatin A (TSA) was shown to enhance the activity of other antifungal agents acting on membrane synthesis, including terbinafine, it had no effect on the activities of amphotericin B and 5-fluorocytosine (Smith and Edlind, 2002)
Sodium valproate, an organic compound used as an anticonvulsive agent which has been shown to be a HDAC inhibitor, used in combination with amphotericin B showed synergistic antifungal activity on biofilms produced by C. albicans, C. krusei, and C. parapsilosis (Göttlicher et al, 2001; Phiel et al, 2001; Al-Dhaheri and Douglas, 2010)

Summary

Sirtuin

2001 Hnisz et al, 2009 Srikantha et al, 2001 Srikantha et al, 2001. Klar et al, 2001; Srikantha et al, 2001; Hnisz et al, 2009; Zacchi et al, 2010 Srikantha et al, 2001 Klar et al, 2001; Maglott et al, 2007; Fu et al, 2008; Nobile et al, 2012 Maglott et al, 2007; Hnisz et al, 2009 Maglott et al, 2007; Hnisz et al, 2009; Nobile et al, 2012 Enjalbert et al, 2006; Maglott et al, 2007; Wurtele et al, 2010; Singh et al, 2011; Stevenson and Liu, 2011 Uhl et al, 2003; Maglott et al, 2007; Hnisz et al, 2009, 2010 promotes filamentous elongation by triggering the expression of the master regulator UME6, a key factor in hyphal differentiation (Lee et al, 2015). 2001 Hnisz et al, 2009 Srikantha et al, 2001 Srikantha et al, 2001.

Hda1 type III Sirtuin

Findings

CONCLUSION