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 (HTS) 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, to evaluate the in vivo toxicity and efficacy of five poorly water-soluble nitronaphthofuran derivatives, which were recently identified to possess anti-tuberculosis activity in vitro. To aid solubilization compounds were formulated in biocompatible polymeric micelles (PM). 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 in vivo toxicity and efficacy of new anti-TB compounds during early stages of drug development. Thus, this model is well suited to pinpoint promising compounds for further development.
The zebrafish embryo as an in vivo model for screening nanoparticle-formulated lipophilic anti-tuberculosis compounds
These authors contributed equally
- Award Group:
- Funder(s): European Research Council
- Award Id(s): NAREB Project 604237
- Funder(s):
- Award Group:
- Funder(s): H2020 Marie Sk̢odowska-Curie Actions
- Award Id(s): 609020
- Funder(s):
- Award Group:
- Funder(s): Norges Forskningsråd
- Award Id(s): 275873
- Funder(s):
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Nils-Jørgen Knudsen Dal, Martin Speth, Kerstin Johann, Matthias Barz, Claire Beauvineau, Jens Wohlmann, Federico Fenaroli, Brigitte Gicquel, Gareth Griffiths, Noelia Alonso-Rodriguez; The zebrafish embryo as an in vivo model for screening nanoparticle-formulated lipophilic anti-tuberculosis compounds. Dis Model Mech 2021; dmm.049147. doi: https://doi.org/10.1242/dmm.049147
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