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

• Published in: Scientific reports 2018-08, Vol.8 (1), p.12664-9, Article 12664
• Main Authors: Soto, Ramón, Perez-Herran, Esther, Rodriguez, Beatriz, Duma, Bogdan M., Cacho-Izquierdo, Monica, Mendoza-Losana, Alfonso, Lelievre, Joel, Aguirre, David Barros, Ballell, Lluis, Cox, Liam R., Alderwick, Luke J., Besra, Gurdyal S.
• Format: Article
• Language: English
• Subjects: 631/326/22/1290; 692/308/153; 82; 82/47; Aminoacylation; Antitubercular Agents - pharmacology; Aspartate-tRNA ligase; Aspartate-tRNA Ligase - antagonists & inhibitors; Aspartate-tRNA Ligase - metabolism; Bacillus Calmette-Guerin vaccine; BCG; Chemotherapy; Drug Evaluation, Preclinical; Drug resistance; Enzyme Inhibitors - pharmacology; HIV; Human immunodeficiency virus; Humanities and Social Sciences; Infectious diseases; Low income areas; Microbial Sensitivity Tests; multidisciplinary; Mycobacterium bovis - drug effects; Mycobacterium bovis - enzymology; Mycobacterium tuberculosis; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - enzymology; Pandemics; Protein biosynthesis; Protein synthesis; Science; Science (multidisciplinary); tRNA; Tuberculosis
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-31157-3

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 tuberculosi s , 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.