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The zebrafish embryo as an in vivo model for screening nanoparticle-formulated lipophilic anti-tuberculosis compounds

With the increasing emergence of drug-resistant Mycobacterium tuberculosis strains, new and effective antibiotics against tuberculosis (TB) are urgently needed. However, the high frequency of poorly water-soluble compounds among hits in high-throughput drug screening campaigns is a major obstacle in...

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Autores principales: Knudsen Dal, Nils-Jørgen, Speth, Martin, Johann, Kerstin, Barz, Matthias, Beauvineau, Claire, Wohlmann, Jens, Fenaroli, Federico, Gicquel, Brigitte, Griffiths, Gareth, Alonso-Rodriguez, Noelia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Company of Biologists Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8807572/
https://www.ncbi.nlm.nih.gov/pubmed/34842273
http://dx.doi.org/10.1242/dmm.049147
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author Knudsen Dal, Nils-Jørgen
Speth, Martin
Johann, Kerstin
Barz, Matthias
Beauvineau, Claire
Wohlmann, Jens
Fenaroli, Federico
Gicquel, Brigitte
Griffiths, Gareth
Alonso-Rodriguez, Noelia
author_facet Knudsen Dal, Nils-Jørgen
Speth, Martin
Johann, Kerstin
Barz, Matthias
Beauvineau, Claire
Wohlmann, Jens
Fenaroli, Federico
Gicquel, Brigitte
Griffiths, Gareth
Alonso-Rodriguez, Noelia
author_sort Knudsen Dal, Nils-Jørgen
collection PubMed
description With the increasing emergence of drug-resistant Mycobacterium tuberculosis strains, new and effective antibiotics against tuberculosis (TB) are urgently needed. However, the high frequency of poorly water-soluble compounds among hits in high-throughput drug screening campaigns is a major obstacle in drug discovery. Moreover, in vivo testing using conventional animal TB models, such as mice, is time consuming and costly, and represents a major bottleneck in lead compound discovery and development. Here, we report the use of the zebrafish embryo TB model for evaluating the in vivo toxicity and efficacy of five poorly water-soluble nitronaphthofuran derivatives, which were recently identified as possessing anti-TB activity in vitro. To aid solubilization, compounds were formulated in biocompatible polymeric micelles (PMs). Three of the five PM-formulated nitronaphthofuran derivatives showed low toxicity in vivo, significantly reduced bacterial burden and improved survival in infected zebrafish embryos. We propose the zebrafish embryo TB-model as a quick and sensitive tool for evaluating the in vivo toxicity and efficacy of new anti-TB compounds during early stages of drug development. Thus, this model is well suited for pinpointing promising compounds for further development.
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spelling pubmed-88075722022-02-02 The zebrafish embryo as an in vivo model for screening nanoparticle-formulated lipophilic anti-tuberculosis compounds Knudsen Dal, Nils-Jørgen Speth, Martin Johann, Kerstin Barz, Matthias Beauvineau, Claire Wohlmann, Jens Fenaroli, Federico Gicquel, Brigitte Griffiths, Gareth Alonso-Rodriguez, Noelia Dis Model Mech Research Article With the increasing emergence of drug-resistant Mycobacterium tuberculosis strains, new and effective antibiotics against tuberculosis (TB) are urgently needed. However, the high frequency of poorly water-soluble compounds among hits in high-throughput drug screening campaigns is a major obstacle in drug discovery. Moreover, in vivo testing using conventional animal TB models, such as mice, is time consuming and costly, and represents a major bottleneck in lead compound discovery and development. Here, we report the use of the zebrafish embryo TB model for evaluating the in vivo toxicity and efficacy of five poorly water-soluble nitronaphthofuran derivatives, which were recently identified as possessing anti-TB activity in vitro. To aid solubilization, compounds were formulated in biocompatible polymeric micelles (PMs). Three of the five PM-formulated nitronaphthofuran derivatives showed low toxicity in vivo, significantly reduced bacterial burden and improved survival in infected zebrafish embryos. We propose the zebrafish embryo TB-model as a quick and sensitive tool for evaluating the in vivo toxicity and efficacy of new anti-TB compounds during early stages of drug development. Thus, this model is well suited for pinpointing promising compounds for further development. The Company of Biologists Ltd 2022-01-26 /pmc/articles/PMC8807572/ /pubmed/34842273 http://dx.doi.org/10.1242/dmm.049147 Text en © 2022. Published by The Company of Biologists Ltd https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Research Article
Knudsen Dal, Nils-Jørgen
Speth, Martin
Johann, Kerstin
Barz, Matthias
Beauvineau, Claire
Wohlmann, Jens
Fenaroli, Federico
Gicquel, Brigitte
Griffiths, Gareth
Alonso-Rodriguez, Noelia
The zebrafish embryo as an in vivo model for screening nanoparticle-formulated lipophilic anti-tuberculosis compounds
title The zebrafish embryo as an in vivo model for screening nanoparticle-formulated lipophilic anti-tuberculosis compounds
title_full The zebrafish embryo as an in vivo model for screening nanoparticle-formulated lipophilic anti-tuberculosis compounds
title_fullStr The zebrafish embryo as an in vivo model for screening nanoparticle-formulated lipophilic anti-tuberculosis compounds
title_full_unstemmed The zebrafish embryo as an in vivo model for screening nanoparticle-formulated lipophilic anti-tuberculosis compounds
title_short The zebrafish embryo as an in vivo model for screening nanoparticle-formulated lipophilic anti-tuberculosis compounds
title_sort zebrafish embryo as an in vivo model for screening nanoparticle-formulated lipophilic anti-tuberculosis compounds
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8807572/
https://www.ncbi.nlm.nih.gov/pubmed/34842273
http://dx.doi.org/10.1242/dmm.049147
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