Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2015 Feb 16:6:96.
doi: 10.3389/fmicb.2015.00096. eCollection 2015.

Histone deacetylase inhibition as an alternative strategy against invasive aspergillosis

Frédéric Lamoth  1 , Praveen R Juvvadi  2 , William J Steinbach  3
Affiliations

Histone deacetylase inhibition as an alternative strategy against invasive aspergillosis

Frédéric Lamoth et al. Front Microbiol. .

Abstract

Invasive aspergillosis (IA) is a life-threatening infection due to Aspergillus fumigatus and other Aspergillus spp. Drugs targeting the fungal cell membrane (triazoles, amphotericin B) or cell wall (echinocandins) are currently the sole therapeutic options against IA. Their limited efficacy and the emergence of resistance warrant the identification of new antifungal targets. Histone deacetylases (HDACs) are enzymes responsible of the deacetylation of lysine residues of core histones, thus controlling chromatin remodeling and transcriptional activation. HDACs also control the acetylation and activation status of multiple non-histone proteins, including the heat shock protein 90 (Hsp90), an essential molecular chaperone for fungal virulence and antifungal resistance. This review provides an overview of the different HDACs in Aspergillus spp. as well as their respective contribution to total HDAC activity, fungal growth, stress responses, and virulence. The potential of HDAC inhibitors, currently under development for cancer therapy, as novel alternative antifungal agents against IA is discussed.

Keywords: Aspergillus fumigatus; antifungal resistance; antifungal therapy; heat shock protein 90; lysine deacetylases; trichostatin A.

PubMed Disclaimer

Figures

FIGURE 1
FIGURE 1
Schematic representation of the role of the classical histone deacetylases (HDACs) in Aspergillus fumigatus. Classical HDACs in Aspergillus spp. include RpdA and HdaA, contributing to the major part of total HDAC activity, and HosA and HosB, contributing to a minor part. RpdA and HosA belong to class 1. HdaA belongs to class 2. HosB was proposed as the only member of a distinct class. In the nucleus, HDACs deacetylate core histones, which results in chromatin remodeling and transcriptional regulation of the expression of secondary metabolites and multiple proteins. They also regulate the function of other nuclear proteins involved in DNA replication, DNA repair, nuclear transport, or cell cycle. HDACs also deacetylate and control the activation of multiple cytosolic proteins, including the heat shock protein 90 (Hsp90), which is essential for fungal growth and stress responses. HDACs thus contribute to fungal development and environmental adaptation in multiple ways. Trichostatin A and other hydroxamate analogs inhibit both class 1 and class 2 HDACs (with the exception of HosB) displaying antifungal activity against A. fumigatus and potentiating (<) the effect of cell wall inhibitors such as the echinocandins. MGCD290 is a specific inhibitor of HosA with poor intrinsic antifungal activity, but potentiates the effect of cell membrane inhibitors such as the azoles.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Augenbraun M., Livingston J., Parker R., Lederman S., Chavoustie S., Morgan F., et al. (2013). “Fluconazole and MGCD290 in vulvo vaginal candidiasis (VVC): results from a randomized phase II study (1330),” in IDWeek 2013, October 2–6, 2013, San Francisco, CA.
    1. Baidyaroy D., Brosch G., Ahn J. H., Graessle S., Wegener S., Tonukari N. J., et al. (2001). A gene related to yeast HOS2 histone deacetylase affects extracellular depolymerase expression and virulence in a plant pathogenic fungus. Plant Cell 13, 1609–1624. 10.1105/tpc.13.7.1609 - DOI - PMC - PubMed
    1. Bali P., Pranpat M., Bradner J., Balasis M., Fiskus W., Guo F., et al. (2005). Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90: a novel basis for antileukemia activity of histone deacetylase inhibitors. J. Biol. Chem. 280, 26729–26734. 10.1074/jbc.C500186200 - DOI - PubMed
    1. Blum G., Kainzner B., Grif K., Dietrich H., Zelger B., Sonnweber T., et al. (2013). In vitro and in vivo role of heat shock protein 90 in Amphotericin B resistance of Aspergillus terreus. Clin. Microbiol. Infect. 19, 50–55. 10.1111/j.1469-0691.2012.03848.x - DOI - PubMed
    1. Brosch G., Loidl P., Graessle S. (2008). Histone modifications and chromatin dynamics: a focus on filamentous fungi. FEMS Microbiol. Rev. 32, 409–439. 10.1111/j.1574-6976.2007.00100.x - DOI - PMC - PubMed

LinkOut - more resources