Discovery of a novel polyaminocarboxylate compound able to successfully treat invasive pulmonary aspergillosis in a murine model by interfering with fungal zinc metabolism

P Laskaris1, JA Calera2, G Jouvion3, L Du Merle4, H Munier-Lehmann5, F Suzenet6, R Alves de Sousa7, J.-P Latgé8, J.-M Cavaillon1, O Ibrahim-Granet1

Author address: 

1 Cytokines & Inflammationn, Institut Pasteur, Paris, France; 2 Departamento de Microbiología y Genética, Instituto de Biologia Funcional y Genómica (IBFG), Salamanca, Spain; 3 Human Histology and animal models, Institut Pasteur, Paris, France; 4 Biology of gram positive pathogens, Institut Pasteur, Paris, France; 5 Chemistry and Biocatalysis Group: Biochemistry and screening, Institut Pasteur, Paris, France 6UMR CNRS 7311, Icoa Université d'Orléans, Orléans , France; 7 Laboratoire de chimie et biochimie pharmacologiques et toxicologiques - UMR, Université Paris Descartes, Paris , France; 8 Aspergillus Unit, Institut Pasteur, Paris, France.

Abstract: 

Purpose: Aspergillus fumigatus can cause pulmonary aspergillosis in immunocompromised patients and is associated with a high mortality rate due to the lack of reliable treatment options. This opportunistic pathogen requires zinc in order to grow and cause virulence. Novel compounds that interfere with fungal zinc metabolism may therefore be of therapeutic interest.

Methods: To identify compounds affecting zinc metabolism, we screened chemical libraries containing 59223 small molecules using a resazurin assay that compared the effects of the biomolecules on an A. fumigatus wild type strain grown under zinc-limited conditions and on a triple zinc transporters knockout strain grown under zinc-replete conditions.

Results: The screen selected 116 molecules that were then subject to luminescence assays and hyphal length measurements to confirm their activity. The toxicity of the selected biomolecules was investigated on HeLa cells and mice. This phase selected 7 compounds, 2 of which were pyrazolones, 3 were porphyrins and 2 were polyaminocarboxylates. All three groups are known to have the ability to bind metal ions. One of the polyaminocarboxylates was able to significantly improve the survival of immunosuppressed mice suffering from pulmonary aspergillosis. 

Conclusion: This two-tier screening approach thus led to the identification of a novel small molecule with in vivo fungicidal effects and low toxicity that may lead to the development of new treatment options for fungal infections either by administration of this compound as a monotherapy or as part of a combination therapy.

2018

abstract No: 

145

Full conference title: 

The 8th Advances Against Aspergillus, Lisbon Conference Center, Lisbon, Portugal
    • AAA 8th (2018)