Anti‐tuberculosis effect of isoniazid scales accurately from zebrafish to humans

Wijk, Rob C. van; Hu, Wanbin; Dijkema, Sharka M; Berg, Dirk–Jan van den; Liu, Jeremy; Bahi, Rida; Verbeek, Fons J.; Simonsson, Ulrika S. H.; Spaink, Herman P.; Graaf, Piet H. van der; Krekels, Elke H. J.

doi:10.1111/bph.15247

Cited by 10 publications

(2 citation statements)

References 53 publications

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“…Recently, a proof-of-concept study from van Wijk et al (2020b) showed that the isoniazid concentration in blood was only 20% of the external drug concentration. Using pharmacokinetic-pharmacodynamic modeling, the authors described the exposure-response relationship and concluded that the early bactericidal effect of isoniazid in human infections translates to the responses observed in the zebrafish model ( van Wijk et al, 2020b ). A similar study was performed on paracetamol, showing that blood concentrations in the embryo were only 10% of the external paracetamol concentration in the fish water ( Van Wijk et al, 2019b ).…”

Section: Discussionmentioning

confidence: 99%

An anti-tuberculosis compound screen using a zebrafish infection model identifies an aspartyl-tRNA synthetase inhibitor

Habjan

Gallant

et al. 2021

Disease Models &Amp; Mechanisms

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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.

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Section: Discussionmentioning

confidence: 99%

An anti-tuberculosis compound screen using a zebrafish infection model identifies an aspartyl-tRNA synthetase inhibitor

Habjan

Gallant

et al. 2021

Disease Models &Amp; Mechanisms

View full text Add to dashboard Cite

show abstract

“…This was recently illustrated in the field of tuberculosis, a disease that is studied in zebrafish larvae infected with M. marinum, a close relative of the human pathogen M. tuberculosis. By correcting for differences in drug sensitivity between the two bacterial species and differences in the growth phase of the bacterial infections in larvae and humans, findings in zebrafish larvae on the efficacy of isoniazid were successfully translated to humans [120]. Similar approaches could be applied in the research on neonatal sepsis to overcome potential issues arising from differences in maturation and function of immunological cell types or signaling pathways, or from differences in body temperature.…”

Section: Future Perspectivesmentioning

confidence: 99%