The main problem of tuberculosis treatment is its multi-resistance to existing antibiotics. Since Ukraine belongs to the top 10 countries in the world with the highest level of multi-drug resistant tuberculosis, the development of novel antituberculosis agents with lower possibility for resistance occurrence is vital.

Unfortunately, the development of novel antituberculosis agents has been limited. Only three novel antibiotics - bedaquiline, delamanid, and pretomanid - have been approved for clinical use in more than forty years. Recently, cases of resistance to these antibiotics have been reported. Therefore, the search for novel molecular targets and the development of novel strategies to overcome Mycobacterium tuberculosis resistance has become a challenging task for modern science.

Our manuscript describes the novel class of chemical compounds with novel molecular mechanism of action which target M. tuberculosis leucyl-tRNA synthetase and methionyl-tRNA synthetase (enzymes involved in protein biosynthesis), that have potential for further development of antimicrobial drugs.

To date, only a few inhibitors of mycobacterial leucyl- and methionyl-tRNA synthetase targeting aminoacyl-adenylate binding site have been reported among some adenylate analogs and previously published by us: N-benzylidene-N′-thiazol-2-yl-hydrazine (MedChemComm 2019) and 3-Phenyl-5-(1-phenyl-1H-[1,2,3]triazol-4-yl)-[1,2,4]oxadiazole (J Comput Aided Mol Des 2019) derivatives. However, inhibitors among N-benzylidene-N′-thiazol-2-yl-hydrazines have poor solubility and reported inhibitor 3-(3-chloro-4-methoxy-phenyl)-5-[3-(4-fuoro-phenyl)-[1,2,4]oxadiazol-5-yl]-3H-[1,2,3]triazol-4-yl-amine does not reveal antibacterial activity.

In this article we report the derivatives of 3-Phenyl-5-(1-phenyl-1H-[1,2,3]triazol-4-yl)-[1,2,4]oxadiazole which possess antibacterial activity toward resistant strains of M. tuberculosis. Therefore, the found compounds may be the basis for further optimization in order to find effective non-toxic antituberculosis agents. We believe that these results will help other Ukrainian and international scientists in the search for novel antibiotic agents and targets.

This work was supported by the National Academy of Sciences of Ukraine grant for young scientists, National Research Fund of Ukraine Grant “Leading and Young Scientists Research Support”, and also by the National Institutes of Allergy and Infectious Diseases (Preclinical Service Contract).

 - Mariia Rybak, Research Fellow, Department of Protein Synthesis Enzymology, Institute of Molecular Biology and Genetics of the NAS of Ukraine

Discovery of novel antituberculosis agents among 3-phenyl-5-(1-phenyl-1H-[1,2,3]triazol-4-yl)-[1,2,4]oxadiazole derivatives targeting aminoacyl-tRNA synthetases - https://www.nature.com/articles/s41598-021-86562-y (Published 30 March 2021)