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

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 gluco...

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Autores principales: Mor, Visesato, Rella, Antonella, Farnoud, Amir M., Singh, Ashutosh, Munshi, Mansa, Bryan, Arielle, Naseem, Shamoon, Konopka, James B., Ojima, Iwao, Bullesbach, Erika, Ashbaugh, Alan, Linke, Michael J., Cushion, Melanie, Collins, Margaret, Ananthula, Hari Krishna, Sallans, Larry, Desai, Pankaj B., Wiederhold, Nathan P., Fothergill, Annette W., Kirkpatrick, William R., Patterson, Thomas, Wong, Lai Hong, Sinha, Sunita, Giaever, Guri, Nislow, Corey, Flaherty, Patrick, Pan, Xuewen, Cesar, Gabriele Vargas, de Melo Tavares, Patricia, Frases, Susana, Miranda, Kildare, Rodrigues, Marcio L., Luberto, Chiara, Nimrichter, Leonardo, Del Poeta, Maurizio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Microbiology 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4479701/
https://www.ncbi.nlm.nih.gov/pubmed/26106079
http://dx.doi.org/10.1128/mBio.00647-15
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author Mor, Visesato
Rella, Antonella
Farnoud, Amir M.
Singh, Ashutosh
Munshi, Mansa
Bryan, Arielle
Naseem, Shamoon
Konopka, James B.
Ojima, Iwao
Bullesbach, Erika
Ashbaugh, Alan
Linke, Michael J.
Cushion, Melanie
Collins, Margaret
Ananthula, Hari Krishna
Sallans, Larry
Desai, Pankaj B.
Wiederhold, Nathan P.
Fothergill, Annette W.
Kirkpatrick, William R.
Patterson, Thomas
Wong, Lai Hong
Sinha, Sunita
Giaever, Guri
Nislow, Corey
Flaherty, Patrick
Pan, Xuewen
Cesar, Gabriele Vargas
de Melo Tavares, Patricia
Frases, Susana
Miranda, Kildare
Rodrigues, Marcio L.
Luberto, Chiara
Nimrichter, Leonardo
Del Poeta, Maurizio
author_facet Mor, Visesato
Rella, Antonella
Farnoud, Amir M.
Singh, Ashutosh
Munshi, Mansa
Bryan, Arielle
Naseem, Shamoon
Konopka, James B.
Ojima, Iwao
Bullesbach, Erika
Ashbaugh, Alan
Linke, Michael J.
Cushion, Melanie
Collins, Margaret
Ananthula, Hari Krishna
Sallans, Larry
Desai, Pankaj B.
Wiederhold, Nathan P.
Fothergill, Annette W.
Kirkpatrick, William R.
Patterson, Thomas
Wong, Lai Hong
Sinha, Sunita
Giaever, Guri
Nislow, Corey
Flaherty, Patrick
Pan, Xuewen
Cesar, Gabriele Vargas
de Melo Tavares, Patricia
Frases, Susana
Miranda, Kildare
Rodrigues, Marcio L.
Luberto, Chiara
Nimrichter, Leonardo
Del Poeta, Maurizio
author_sort Mor, Visesato
collection PubMed
description 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.
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spelling pubmed-44797012015-06-29 Identification of a New Class of Antifungals Targeting the Synthesis of Fungal Sphingolipids Mor, Visesato Rella, Antonella Farnoud, Amir M. Singh, Ashutosh Munshi, Mansa Bryan, Arielle Naseem, Shamoon Konopka, James B. Ojima, Iwao Bullesbach, Erika Ashbaugh, Alan Linke, Michael J. Cushion, Melanie Collins, Margaret Ananthula, Hari Krishna Sallans, Larry Desai, Pankaj B. Wiederhold, Nathan P. Fothergill, Annette W. Kirkpatrick, William R. Patterson, Thomas Wong, Lai Hong Sinha, Sunita Giaever, Guri Nislow, Corey Flaherty, Patrick Pan, Xuewen Cesar, Gabriele Vargas de Melo Tavares, Patricia Frases, Susana Miranda, Kildare Rodrigues, Marcio L. Luberto, Chiara Nimrichter, Leonardo Del Poeta, Maurizio mBio Research Article 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. American Society of Microbiology 2015-06-23 /pmc/articles/PMC4479701/ /pubmed/26106079 http://dx.doi.org/10.1128/mBio.00647-15 Text en Copyright © 2015 Mor et al. http://creativecommons.org/licenses/by-nc-sa/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported license (http://creativecommons.org/licenses/by-nc-sa/3.0/) , which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Mor, Visesato
Rella, Antonella
Farnoud, Amir M.
Singh, Ashutosh
Munshi, Mansa
Bryan, Arielle
Naseem, Shamoon
Konopka, James B.
Ojima, Iwao
Bullesbach, Erika
Ashbaugh, Alan
Linke, Michael J.
Cushion, Melanie
Collins, Margaret
Ananthula, Hari Krishna
Sallans, Larry
Desai, Pankaj B.
Wiederhold, Nathan P.
Fothergill, Annette W.
Kirkpatrick, William R.
Patterson, Thomas
Wong, Lai Hong
Sinha, Sunita
Giaever, Guri
Nislow, Corey
Flaherty, Patrick
Pan, Xuewen
Cesar, Gabriele Vargas
de Melo Tavares, Patricia
Frases, Susana
Miranda, Kildare
Rodrigues, Marcio L.
Luberto, Chiara
Nimrichter, Leonardo
Del Poeta, Maurizio
Identification of a New Class of Antifungals Targeting the Synthesis of Fungal Sphingolipids
title Identification of a New Class of Antifungals Targeting the Synthesis of Fungal Sphingolipids
title_full Identification of a New Class of Antifungals Targeting the Synthesis of Fungal Sphingolipids
title_fullStr Identification of a New Class of Antifungals Targeting the Synthesis of Fungal Sphingolipids
title_full_unstemmed Identification of a New Class of Antifungals Targeting the Synthesis of Fungal Sphingolipids
title_short Identification of a New Class of Antifungals Targeting the Synthesis of Fungal Sphingolipids
title_sort identification of a new class of antifungals targeting the synthesis of fungal sphingolipids
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4479701/
https://www.ncbi.nlm.nih.gov/pubmed/26106079
http://dx.doi.org/10.1128/mBio.00647-15
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