Identification and characterization of aspartyl-tRNA synthetase inhibitors against Mycobacterium tuberculosis by an integrated whole-cell target-based approach.

Scientific Reports
Ramón SotoGurdyal S Besra

Abstract

Mycobacterium tuberculosis, the causative agent of tuberculosis, has surpassed HIV as the leading cause of death due to an infectious disease worldwide, being responsible for more than 1.5 million deaths in low-income countries. In response to a pandemic threat by drug resistant strains, the tuberculosis research community is searching for new chemical entities with novel mechanisms of action to avoid drug resistance and shorten treatment regimens using combinatorial chemotherapy. Herein, we have identified several novel chemical scaffolds, GSK97C (spiro-oxazolidin-2-one), GSK93A (2-amino-1,3-thiazole, GSK85A and GSK92A (enamides), which target M. tuberculosis aspartyl-tRNA synthetase (Mt-AspRS), an essential component of the protein synthesis machinery of tuberculosis, using a whole-cell target-based screening strategy against a genetically modified Mycobacterium bovis BCG strain. We also provide further evidence of protein inhibition and inhibitor profiling through a classical aminoacylation reaction and a tRNA-independent assay, respectively. Altogether, our results have identified a number of hit new molecules with novel mechanism of action for further development through medicinal chemistry as hits and leads.

References

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Citations

Mar 20, 2021·International Journal of Biological Macromolecules·Girish Ch PanigrahiInsaf Ahmed Qureshi
May 17, 2021·Chemical Biology & Drug Design·Umar NdagiNdumiso N Mhlongo
Aug 3, 2021·ACS Chemical Biology·Jianrong LiuWenhan Lin
Sep 20, 2021·Drug Discovery Today·Liu YangTingjun Hou

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Methods Mentioned

BETA
aminoacylation
acylation

Software Mentioned

Graph Pad Prism
GraphPad Prism
Excel
Spotfire
TIBCO Spotfire

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