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© Institut Pasteur
Cristaux de cellulase, enzyme purifiée de Clostridium thermocellum permettant la digestion de la cellulose. Image colorisée.
Publication : Antimicrobial agents and chemotherapy

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

Scientific Fields
Diseases
Organisms
Applications
Technique

Published in Antimicrobial agents and chemotherapy - 25 May 2018

Laskaris P, Vicentefranqueira R, Helynck O, Jouvion G, Calera JA, du Merle L, Suzenet F, Buron F, de Sousa RA, Mansuy D, Cavaillon JM, Latgé JP, Munier-Lehmann H, Ibrahim-Granet O

Link to Pubmed [PMID] – 29632009

Antimicrob. Agents Chemother. 2018 Jun;62(6)

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 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 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 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.

https://www.ncbi.nlm.nih.gov/pubmed/29632009