A Novel Polyaminocarboxylate Compound To Treat Murine Pulmonary Aspergillosis by Interfering with Zinc Metabolism
In: ISSN: 0066-4804, 2018
Online
academicJournal
Zugriff:
International audience ; Aspergillus fumigatus can cause pulmonary aspergillosis in immunocompromised patients and is associated with a high mortality rate due to a lack of reliable treatment options. This opportunistic pathogen requires zinc in order to grow and cause disease. Novel compounds that interfere with fungal zinc metabolism may therefore be of therapeutic interest. We screened chemical libraries containing 59,223 small molecules using a resazurin assay that compared their effects on an A. fumigatus wild-type strain grown under zinc-limiting conditions and on a zinc transporter knockout strain grown under zinc-replete conditions to identify compounds affecting zinc metabolism. After a first screen, 116 molecules were selected whose inhibitory effects on fungal growth were further tested by using luminescence assays and hyphal length measurements to confirm their activity, as well as by toxicity assays on HeLa cells and mice. Six compounds were selected following a rescreening, of which two were pyrazolones, two were porphyrins, and two were polyaminocarboxylates. All three groups showed good in vitro activity, but only one of the polyaminocarboxylates was able to significantly improve the survival of immunosuppressed mice suffering from pulmonary aspergillosis. This two-tier screening approach led us to the identification of a novel small molecule with in vivo fungicidal effects and low murine toxicity that may lead to the development of new treatment options for fungal infections by administration of this compound either as a monotherapy or as part of a combination therapy.
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A Novel Polyaminocarboxylate Compound To Treat Murine Pulmonary Aspergillosis by Interfering with Zinc Metabolism
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Autor/in / Beteiligte Person: | Laskaris, Paris ; Vicentefranqueira, Rocío ; Helynck, Olivier ; Jouvion, Grégory ; Calera, José Antonio ; Du Merle, Laurence ; Suzenet, Franck ; Buron, Frédéric ; de Sousa, Rodolphe Alves ; Mansuy, Daniel ; Cavaillon, Jean-Marc ; Latgé, Jean-Paul ; Munier-Lehmann, Hélène ; Ibrahim-Granet, Oumaïma ; Cytokines et Inflammation ; Institut Pasteur Paris (IP) ; Universidad de Salamanca ; Chimie et Biocatalyse ; Institut Pasteur Paris (IP)-Institut de Chimie - CNRS Chimie (INC-CNRS)-Centre National de la Recherche Scientifique (CNRS) ; Histopathologie humaine et Modèles animaux ; Biologie des Bactéries pathogènes à Gram-positif ; Institut Pasteur Paris (IP)-Centre National de la Recherche Scientifique (CNRS) ; Institut de Chimie Organique et Analytique (ICOA) ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie - CNRS Chimie (INC-CNRS)-Centre National de la Recherche Scientifique (CNRS) ; Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601) ; Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie - CNRS Chimie (INC-CNRS)-Centre National de la Recherche Scientifique (CNRS) ; Aspergillus ; O.I.-G., H.M.-L., and J.-P.L. were supported by the PTR468 funding program. P.L. received funding from PTR468 and CARNOT MS for a postdoctoral fellowship. J.A.C. was supported by the Spanish Ministry of Economy and Competitiveness through grant SAF2013-48382 R. ; We thank Yves Janin for the synthesis of the pyrazolones Pyr05 and Pyr11, Constance Bochot and Pierrette Battioni of UMR8601 for the supply of Por06 and Por07 compounds, and the National Library of National Chemistry for providing access to the complete database for screening. We thank Hervé Waxin from the Institut Pasteur education department and Marie-Anne Nicolas from the Institut Pasteur Photonic BioImaging (UTechS PBI) for their assistance in live imaging. |
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Zeitschrift: | ISSN: 0066-4804, 2018 |
Veröffentlichung: | HAL CCSD ; American Society for Microbiology, 2018 |
Medientyp: | academicJournal |
DOI: | 10.1128/AAC.02510-17 |
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