Screening of antitubercular compound library identifies novel shikimate kinase inhibitors of Mycobacterium tuberculosis
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Shikimate kinase of Mycobacterium tuberculosis is involved in the biosynthesis of aromatic amino acids through shikimate pathway. The enzyme is essential for the survival of M. tuberculosis and is absent from mammals, thus providing an excellent opportunity for identifying new chemical entities to combat tuberculosis with a novel mechanism of action. In this study, an antitubercular library of 1000 compounds was screened against M. tuberculosis shikimate kinase (MtSK). This effort led to the identification of 20 inhibitors, among which five promising leads exhibited half maximal inhibitory concentration (IC50) values below 10 μM. The most potent inhibitor (“5631296”) showed an IC50 value of 5.10 μM ± 0.6. The leads were further evaluated for the activity against multidrug-resistant (MDR)-TB, Gram-positive and Gram-negative bacterial strains, mode of action, docking simulations, and combinatorial study with three frontline anti-TB drugs. Compound “5491210” displayed a nearly synergistic activity with rifampicin, isoniazid, and ethambutol while compound “5631296” was synergistic with rifampicin. In vitro cytotoxicity against HepG2 cell line was evaluated and barring one compound; all were found to be non-toxic (SI > 10). In order to rule out mitochondrial toxicity, the promising inhibitors were also evaluated for cell cytotoxicity using galactose medium where compounds “5631296” and “5122752” appeared non-toxic. Upon comprehensive analysis, compound “5631296” was found to be the most promising MtSK inhibitor that was safe, synergistic with rifampicin, and bactericidal against M. tuberculosis.
KeywordsMycobacterium tuberculosis Shikimate kinase Antitubercular ChemBridge Docking
The author (VSR) is thankful to the Council of Scientific and Industrial Research (CSIR), New Delhi, for GATE fellowship (7/614/2010-Estt.).
Compliance with ethical standards
This article does not contain any studies with human participants or animals performed by any of the authors.
This work was funded by Council of Scientific and Industrial Research (CSIR), New Delhi, India (Grant no. BSC0205).
Conflict of interest
The authors declare that they have no competing interests.
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