Identification of a New Class of Antifungals Targeting the Synthesis of Fungal Sphingolipids
Open Access
- 1 July 2015
- journal article
- research article
- Published by American Society for Microbiology in mBio
- Vol. 6 (3), e00647-15
- https://doi.org/10.1128/mbio.00647-15
Abstract
Recent estimates suggest that >300 million people are afflicted by serious fungal infections worldwide. Current antifungal drugs are static and toxic and/or have a narrow spectrum of activity. Thus, there is an urgent need for the development of new antifungal drugs. The fungal sphingolipid glucosylceramide (GlcCer) is critical in promoting virulence of a variety of human-pathogenic fungi. In this study, we screened a synthetic drug library for compounds that target the synthesis of fungal, but not mammalian, GlcCer and found two compounds [ N ′-(3-bromo-4-hydroxybenzylidene)-2-methylbenzohydrazide (BHBM) and its derivative, 3-bromo- N ′-(3-bromo-4-hydroxybenzylidene) benzohydrazide (D0)] that were highly effective in vitro and in vivo against several pathogenic fungi. BHBM and D0 were well tolerated in animals and are highly synergistic or additive to current antifungals. BHBM and D0 significantly affected fungal cell morphology and resulted in the accumulation of intracellular vesicles. Deep-sequencing analysis of drug-resistant mutants revealed that four protein products, encoded by genes APL5 , COS111 , MKK1 , and STE2 , which are involved in vesicular transport and cell cycle progression, are targeted by BHBM. IMPORTANCE Fungal infections are a significant cause of morbidity and mortality worldwide. Current antifungal drugs suffer from various drawbacks, including toxicity, drug resistance, and narrow spectrum of activity. In this study, we have demonstrated that pharmaceutical inhibition of fungal glucosylceramide presents a new opportunity to treat cryptococcosis and various other fungal infections. In addition to being effective against pathogenic fungi, the compounds discovered in this study were well tolerated by animals and additive to current antifungals. These findings suggest that these drugs might pave the way for the development of a new class of antifungals.Keywords
This publication has 63 references indexed in Scilit:
- Perturbations to the Ubiquitin Conjugate Proteome in Yeast Δubx Mutants Identify Ubx2 as a Regulator of Membrane Lipid CompositionMolecular & Cellular Proteomics, 2013
- A framework for variation discovery and genotyping using next-generation DNA sequencing dataNature Genetics, 2011
- Knocking out multigene redundancies via cycles of sexual assortment and fluorescence selectionNature Methods, 2011
- Systematic screens of a Candida albicans homozygous deletion library decouple morphogenetic switching and pathogenicityNature Genetics, 2010
- Cryptococcus neoformans cryoultramicrotomy and vesicle fractionation reveals an intimate association between membrane lipids and glucuronoxylomannanFungal Genetics and Biology, 2009
- Adjacent positioning of cellular structures enabled by a Cdc42 GTPase-activating protein–mediated zone of inhibitionThe Journal of cell biology, 2007
- Phosphorylation of Bem2p and Bem3p may contribute to local activation of Cdc42p at bud emergenceThe EMBO Journal, 2007
- Exploration of the Function and Organization of the Yeast Early Secretory Pathway through an Epistatic Miniarray ProfileCell, 2005
- Adaptable adaptors for coated vesiclesTrends in Cell Biology, 2004
- A proteomics approach to understanding protein ubiquitinationNature Biotechnology, 2003