PUBLICATION
Anti-tuberculosis Compound Screen using a Zebrafish Infection Model identifies an Aspartyl-tRNA Synthetase Inhibitor
- Authors
- Habjan, E., Ho, V.Q.T., Gallant, J., Van Stempvoort, G., Jim, K.K., Kuijl, C., Geerke, D.P., Bitter, W., Speer, A.
- ID
- ZDB-PUB-211015-9
- Date
- 2021
- Source
- Disease models & mechanisms 14(12): (Journal)
- Registered Authors
- Bitter, Wilbert
- Keywords
- Aminoacyl-tRNA synthetase, Drug-screening, Infection model, Mycobacterium tuberculosis, Tuberculosis, Zebrafish
- MeSH Terms
-
- Animals
- Aspartate-tRNA Ligase*
- Molecular Docking Simulation
- Mycobacterium tuberculosis*
- Tuberculosis*/drug therapy
- Tuberculosis*/microbiology
- Zebrafish
- PubMed
- 34643222 Full text @ Dis. Model. Mech.
Citation
Habjan, E., Ho, V.Q.T., Gallant, J., Van Stempvoort, G., Jim, K.K., Kuijl, C., Geerke, D.P., Bitter, W., Speer, A. (2021) Anti-tuberculosis Compound Screen using a Zebrafish Infection Model identifies an Aspartyl-tRNA Synthetase Inhibitor. Disease models & mechanisms. 14(12):.
Abstract
Finding new anti-tuberculosis compounds with convincing in vivo activity is an ongoing global challenge to fight the emergence of multi-drug resistant Mycobacterium tuberculosis isolates. In this work, 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-TB 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 possible binding of TBA161 in a pocket adjacent to the catalytic site. This study showed that the zebrafish-infection model is suitable to rapidly identify promising scaffolds with in vivo activity.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping