A Histone Acetyltransferase Inhibitor with Antifungal Activity against CTG clade Candida Species.

Kuchler Kuchler,Tscherner Tscherner

doi:10.3390/microorganisms7070201

Kuchler Kuchler, Tscherner Tscherner

Open Access

https://doi.org/10.3390/microorganisms7070201

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Journal: Microorganisms	Publication Date: Jul 15, 2019
Citations: 5	License type: CC BY 4.0

Affiliation: Max Perutz Labs, Medical University of Vienna

Abstract

Candida species represent one of the most frequent causes of hospital-acquired infections in immunocompromised patient cohorts. Due to a very limited set of antifungals available and an increasing prevalence of drug resistance, the discovery of novel antifungal targets is essential. Targeting chromatin modifiers as potential antifungal targets has gained attention recently, mainly due to their role in regulating virulence in Candida species. Here, we describe a novel activity for the histone acetyltransferase inhibitor Cyclopentylidene-[4-(4-chlorophenyl)thiazol-2-yl)hydrazone (CPTH2) as a specific inhibitor of CTG clade Candida species. Furthermore, we show that CPTH2 has fungicidal activity and protects macrophages from Candida-mediated death. Thus, this work could provide a starting point for the development of novel antifungals specific to CTG clade Candida species.

Highlights

Fungal pathogens represent a major health thread worldwide, causing both superficial and systemic infections in immunocompromised people, causing about 1.5 million deaths each year [1,2]
We aimed to test a set of known histone acetyltransferase inhibitors for their ability to inhibit Hat1
We discovered that the Gcn5 histone acetyltransferases (HATs) inhibitor CPTH2 can potently inhibit growth of pathogenic fungi and even has fungicidal activity

Summary

Introduction

Fungal pathogens represent a major health thread worldwide, causing both superficial and systemic infections in immunocompromised people, causing about 1.5 million deaths each year [1,2]. The majority of Candida infections are caused by members of the so-called CTG clade, a group of species that translate the CUG codon as serine instead of leucine. This group includes Candida albicans, the most frequent cause of candidemia, being responsible for at least 40% of all cases worldwide [3,6]. Even for the quite successful class of echinocandins, recent reports indicate increasing prevalence of resistant Candida species [10,11]. There is an increasing need for discovery of novel antifungal targets

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