Erratum for Mor et al., 'Identification of a New Class of Antifungals Targeting the Synthesis of Fungal Sphingolipids'
| Autor: | Amir M. Farnoud, Hari Krishna Ananthula, Lai Hong Wong, Ashutosh Singh, Visesato Mor, Michael J. Linke, Margaret S. Collins, Susana Frases, Chiara Luberto, Gabriele Vargas Cesar, Xuewen Pan, Corey Nislow, Erika E. Büllesbach, William R. Kirkpatrick, Annette W. Fothergill, Larry Sallans, Alan Ashbaugh, Iwao Ojima, James B. Konopka, Melanie T. Cushion, Marcio L. Rodrigues, Thomas F. Patterson, Leonardo Nimrichter, Arielle M. Bryan, Maurizio Del Poeta, Shamoon Naseem, Patricia de Melo Tavares, Kildare Miranda, Antonella Rella, Sunita Sinha, Nathan P. Wiederhold, Patrick Flaherty, Pankaj B. Desai, Guri Giaever, Mansa Munshi |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Antifungal Agents Drug-Related Side Effects and Adverse Reactions Cell Survival 030106 microbiology Colony Count Microbial Drug Evaluation Preclinical Microbial Sensitivity Tests Computational biology Biology Microbiology Cell Line Mice 03 medical and health sciences Microscopy Electron Transmission Virology Benzyl Compounds Animals Sphingolipids Microbial Viability Molecular Structure Macrophages Candidiasis Fungi Drug Synergism Sphingolipid QR1-502 Biosynthetic Pathways Disease Models Animal Treatment Outcome Identification (biology) Erratum Research Article |
| Zdroj: | mBio mBio, Vol 9, Iss 2, p e00188-18 (2018) mBio, Vol 9, Iss 2 (2018) |
| ISSN: | 2150-7511 2161-2129 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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