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

作者：Visesato Mor, Antonella Rella, Amir Mohammad Farnoud, Ashutosh Singh, Mansa Munshi, Arielle M. Bryan, Shamoon Naseem, James B. Konopka, Iwao Ojima, Erika E. Büllesbach, Alan Ashbaugh, Michael J. Linke, Melanie T. Cushion, Margaret S. Collins, Hari Krishna Ananthula, Larry Sallans, Pankaj B. Desai, Nathan P. Wiederhold, Annette W. Fothergill, William R. Kirkpatrick, Thomas F. Patterson, Lai Hong Wong, Sunita Sinha, Guri N. Giaever, Corey Nislow, Patrick J. Flaherty, Xuewen Pan, Gabriele Vargas, Patricia de Melo Tavares, Susana Frasés, Kildare Rocha de Miranda, Márcio Lourenço Rodrigues, Chiara Luberto, Leonardo Nimrichter, Maurizio Del Poeta · 发表于：mBio · 年份：2015 · DOI：10.1128/mbio.00647-15 · 被引用次数：149 · 研究领域：Sphingolipid Metabolism and Signaling、Pharmacological Receptor Mechanisms and Effects、Lysosomal Storage Disorders Research

UNLABELLED: 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 ph...