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Research Article

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

Visesato Mor, Antonella Rella, Amir M. Farnoud, Ashutosh Singh, Mansa Munshi, Arielle Bryan, Shamoon Naseem, James B. Konopka, Iwao Ojima, Erika Bullesbach, Alan Ashbaugh, Michael J. Linke, Melanie Cushion, Margaret Collins, Hari Krishna Ananthula, Larry Sallans, Pankaj B. Desai, Nathan P. Wiederhold, Annette W. Fothergill, William R. Kirkpatrick, Thomas Patterson, Lai Hong Wong, Sunita Sinha, Guri Giaever, Corey Nislow, Patrick Flaherty, Xuewen Pan, Gabriele Vargas Cesar, Patricia de Melo Tavares, Susana Frases, Kildare Miranda, Marcio L. Rodrigues, Chiara Luberto, Leonardo Nimrichter, Maurizio Del Poeta
Julian E. Davies, Editor
Visesato Mor
Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, USA
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Antonella Rella
Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, USA
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Amir M. Farnoud
Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, USA
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Ashutosh Singh
Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, USA
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Mansa Munshi
Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, USA
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Arielle Bryan
Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, USA
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Shamoon Naseem
Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, USA
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James B. Konopka
Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, USA
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Iwao Ojima
Department of Chemistry and Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, New York, USA
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Erika Bullesbach
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA
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Alan Ashbaugh
Department of Veterans Affairs Medical Center, Cincinnati, Ohio, USA
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Michael J. Linke
Department of Veterans Affairs Medical Center, Cincinnati, Ohio, USAUniversity of Cincinnati College of Medicine, Cincinnati, Ohio, USA
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Melanie Cushion
Department of Veterans Affairs Medical Center, Cincinnati, Ohio, USAUniversity of Cincinnati College of Medicine, Cincinnati, Ohio, USA
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Margaret Collins
University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
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Hari Krishna Ananthula
Department of Pharmaceutical Sciences, University of Cincinnati, Cincinnati, Ohio, USA
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Larry Sallans
Department of Chemistry, University of Cincinnati, Cincinnati, Ohio, USA
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Pankaj B. Desai
Department of Pharmaceutical Sciences, University of Cincinnati, Cincinnati, Ohio, USA
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Nathan P. Wiederhold
Department of Pathology, Fungus Testing Laboratory, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
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Annette W. Fothergill
Department of Pathology, Fungus Testing Laboratory, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
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William R. Kirkpatrick
Division of Infectious Diseases, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
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Thomas Patterson
Division of Infectious Diseases, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
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Lai Hong Wong
Department of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Colombia, Canada
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Sunita Sinha
Department of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Colombia, Canada
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Guri Giaever
Department of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Colombia, Canada
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Corey Nislow
Department of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Colombia, Canada
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Patrick Flaherty
Department of Biomedical Engineering, Worcester Polytechnic Institute, Worcester, Massachusetts, USA
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Xuewen Pan
Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, USA
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Gabriele Vargas Cesar
Instituto de Microbiologia Professor Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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Patricia de Melo Tavares
Instituto de Microbiologia Professor Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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Susana Frases
Laboratório de Ultraestrutura Celular Hertha Meyer, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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Kildare Miranda
Instituto de Microbiologia Professor Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, BrazilDiretoria de Metrologia Aplicada a Ciências da Vida, Instituto Nacional de Metrologia, Qualidade e Tecnologia (INMETRO), Xerém, Rio de Janeiro, Brazil
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Marcio L. Rodrigues
Instituto de Microbiologia Professor Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, BrazilFundação Oswaldo Cruz (Fiocruz), Centro de Desenvolvimento Tecnológico em Saúde (CDTS), Rio de Janeiro, Brazil
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Chiara Luberto
Department of Physiology and Biophysics, Stony Brook University, Stony Brook, New York, USA
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Leonardo Nimrichter
Instituto de Microbiologia Professor Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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Maurizio Del Poeta
Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, USA
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Julian E. Davies
University of British Columbia
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DOI: 10.1128/mBio.00647-15
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This article has a correction. Please see:

  • Erratum for Mor et al., “Identification of a New Class of Antifungals Targeting the Synthesis of Fungal Sphingolipids” - March 13, 2018

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.

  • Copyright © 2015 Mor et al.

This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported license, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Identification of a New Class of Antifungals Targeting the Synthesis of Fungal Sphingolipids
Visesato Mor, Antonella Rella, Amir M. Farnoud, Ashutosh Singh, Mansa Munshi, Arielle Bryan, Shamoon Naseem, James B. Konopka, Iwao Ojima, Erika Bullesbach, Alan Ashbaugh, Michael J. Linke, Melanie Cushion, Margaret Collins, Hari Krishna Ananthula, Larry Sallans, Pankaj B. Desai, Nathan P. Wiederhold, Annette W. Fothergill, William R. Kirkpatrick, Thomas Patterson, Lai Hong Wong, Sunita Sinha, Guri Giaever, Corey Nislow, Patrick Flaherty, Xuewen Pan, Gabriele Vargas Cesar, Patricia de Melo Tavares, Susana Frases, Kildare Miranda, Marcio L. Rodrigues, Chiara Luberto, Leonardo Nimrichter, Maurizio Del Poeta
mBio Jun 2015, 6 (3) e00647-15; DOI: 10.1128/mBio.00647-15

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Identification of a New Class of Antifungals Targeting the Synthesis of Fungal Sphingolipids
Visesato Mor, Antonella Rella, Amir M. Farnoud, Ashutosh Singh, Mansa Munshi, Arielle Bryan, Shamoon Naseem, James B. Konopka, Iwao Ojima, Erika Bullesbach, Alan Ashbaugh, Michael J. Linke, Melanie Cushion, Margaret Collins, Hari Krishna Ananthula, Larry Sallans, Pankaj B. Desai, Nathan P. Wiederhold, Annette W. Fothergill, William R. Kirkpatrick, Thomas Patterson, Lai Hong Wong, Sunita Sinha, Guri Giaever, Corey Nislow, Patrick Flaherty, Xuewen Pan, Gabriele Vargas Cesar, Patricia de Melo Tavares, Susana Frases, Kildare Miranda, Marcio L. Rodrigues, Chiara Luberto, Leonardo Nimrichter, Maurizio Del Poeta
mBio Jun 2015, 6 (3) e00647-15; DOI: 10.1128/mBio.00647-15
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