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Título

A Novel Polyaminocarboxylate Compound To Treat Murine Pulmonary Aspergillosis by Interfering with Zinc Metabolism

AutorLaskaris, Paris; Vicentefranqueira, Rocío CSIC ORCID CVN; Helynck, Olivier; Jouvion, Grégory; Calera, José Antonio CSIC ORCID; Merle, Laurence du; Suzenet, Franck; Buron, Frédéric; Sousa, Rodolphe Alves de; Mansuy, Daniel; Cavaillon, Jean-Marc; Latgé, Jean Paul; Munier-Lehmann, Hélène; Ibrahim-Granet, Oumaima
Palabras claveAspergillus fumigatus
Animal models
Antifungal agents
Antifungal susceptibility testing
Aspergillosis
Bioluminescence
Drug screening
Fungal infection
Immunosuppression
Zinc metabolism
Fecha de publicaciónjun-2018
EditorAmerican Society for Microbiology
CitaciónAntimicrobial Agents and Chemotherapy r 62(6): e02510-17 (2018)
ResumenAspergillus 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.
Versión del editorhttps://doi.org/10.1128/AAC.02510-17
URIhttp://hdl.handle.net/10261/182767
DOI10.1128/AAC.02510-17
ISSN0066-4804
E-ISSN1098-6596
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