Abstract
Finding new anti-tuberculosis compounds with convincing in vivo activity is an ongoing global challenge to fight the emergence of multidrug-resistant Mycobacterium tuberculosis isolates. In this study, we exploited the medium-throughput capabilities of the zebrafish embryo infection model with Mycobacterium marinum as a surrogate for M. tuberculosis. Using a representative set of clinically established drugs, we demonstrate that this model could be predictive and selective for antibiotics that can be administered orally. We further used the zebrafish infection model to screen 240 compounds from an anti-tuberculosis hit library for their in vivo activity and identified 14 highly active compounds. One of the most active compounds was the tetracyclic compound TBA161, which was studied in more detail. Analysis of resistant mutants revealed point mutations in aspS (rv2572c), encoding an aspartyl-tRNA synthetase. The target was genetically confirmed, and molecular docking studies propose the possible binding of TBA161 in a pocket adjacent to the catalytic site. This study shows that the zebrafish infection model is suitable for rapidly identifying promising scaffolds with in vivo activity.
| Original language | English |
|---|---|
| Article number | dmm049145 |
| Journal | DMM Disease Models and Mechanisms |
| Volume | 14 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - Dec 2021 |
Bibliographical note
Funding Information:This work was supported by the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (TTW-NACTAR-16445 to W.B. and the VENI grant 016.Veni.171.090 to A.S.). The Amsterdam Institute for Infection and Immunity supported this work with funding awarded to A.S. The research leading to these results has received funding from the Innovative Medicines Initiative Joint Undertaking under grant agreement n° 115583, resources of which are composed of financial contributions from the European Union Seventh Framework Program (FP7/2007-2013) and the European Federation of Pharmaceutical Industries and Associations companies’ in kind contribution. The European Gram-negative Antibacterial Engine (ENABLE) project is also financially supported by contributions from academic and small-and medium-sized enterprise partners.
Publisher Copyright:
© 2021. Published by The Company of Biologists Ltd.
Funding
This work was supported by the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (TTW-NACTAR-16445 to W.B. and the VENI grant 016.Veni.171.090 to A.S.). The Amsterdam Institute for Infection and Immunity supported this work with funding awarded to A.S. The research leading to these results has received funding from the Innovative Medicines Initiative Joint Undertaking under grant agreement n° 115583, resources of which are composed of financial contributions from the European Union Seventh Framework Program (FP7/2007-2013) and the European Federation of Pharmaceutical Industries and Associations companies’ in kind contribution. The European Gram-negative Antibacterial Engine (ENABLE) project is also financially supported by contributions from academic and small-and medium-sized enterprise partners.
Keywords
- Aminoacyl-tRNA synthetase
- Drug screening
- Infection model
- Mycobacterium tuberculosis
- Tuberculosis
- Zebrafish
