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MBio. 2015 Jun 23;6(3):e00647. doi: 10.1128/mBio.00647-15.

Identification of a New Class of Antifungals Targeting the Synthesis of Fungal Sphingolipids.

Author information

1
Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, USA.
2
Department of Chemistry and Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, New York, USA.
3
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA.
4
Department of Veterans Affairs Medical Center, Cincinnati, Ohio, USA.
5
University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
6
Department of Pharmaceutical Sciences, University of Cincinnati, Cincinnati, Ohio, USA.
7
Department of Chemistry, University of Cincinnati, Cincinnati, Ohio, USA.
8
Department of Pathology, Fungus Testing Laboratory, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
9
Division of Infectious Diseases, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
10
Department of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Colombia, Canada.
11
Department of Biomedical Engineering, Worcester Polytechnic Institute, Worcester, Massachusetts, USA.
12
Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, USA.
13
Instituto de Microbiologia Professor Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
14
Laboratório de Ultraestrutura Celular Hertha Meyer, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
15
Department of Physiology and Biophysics, Stony Brook University, Stony Brook, New York, USA.
16
Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, USA maurizio.delpoeta@stonybrook.edu.

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.

PMID:
26106079
PMCID:
PMC4479701
DOI:
10.1128/mBio.00647-15
[Indexed for MEDLINE]
Free PMC Article

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