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IDENTIFICATION OF A NEW CLASS OF ANTIFUNGALS TARGETING THE SYNTHESIS OF FUNGAL SPHINGOLIPIDS
Autor
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 Lourenço
Luberto, Chiara
Nimrichter, Leonardo
Del Poeta, Maurizio
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 Lourenço
Luberto, Chiara
Nimrichter, Leonardo
Del Poeta, Maurizio
Afiliación
Fundação Oswaldo Cruz. Centro de Desenvolvimento Tecnológico em Saúde. Rio de Janeiro, RJ, Brasil / Universidade Federal do Rio de Janeiro. Instituto de Microbiologia Paulo de Góes. Rio de Janeiro, RJ, Brasil.
Múltipla - ver notas
Múltipla - ver notas
Resumen en ingles
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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