title: Screening of antitubercular compound library identifies novel shikimate kinase inhibitors of Mycobacterium tuberculosis.
abstract: 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.
authors.affiliation: Clinical Microbiology Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu Tawi, 180001, India.|Academy of Scientific & Innovative Research (AcSIR), Anusandhan Bhavan, 2 Rafi Marg, New Delhi, 110001, India.
authors.forename: Vikrant S
authors.initials: VS
authors.lastname: Rajput
authors.affiliation: Discovery Informatics, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu, 180001, India.
authors.forename: Rukmankesh
authors.initials: R
authors.lastname: Mehra
authors.affiliation: Medicinal Chemistry Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu, 180001, India.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Academy of Scientific & Innovative Research (AcSIR), Anusandhan Bhavan, 2 Rafi Marg, New Delhi, 110001, India.|Discovery Informatics, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu, 180001, India.
authors.forename: Amit
authors.initials: A
authors.lastname: Nargotra
authors.affiliation: Academy of Scientific & Innovative Research (AcSIR), Anusandhan Bhavan, 2 Rafi Marg, New Delhi, 110001, India.|Medicinal Chemistry Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu, 180001, India.
authors.forename: Parvinder Pal
authors.initials: PP
authors.lastname: Singh
authors.affiliation: Clinical Microbiology Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu Tawi, 180001, India. iakhan@iiim.res.in.|Academy of Scientific & Innovative Research (AcSIR), Anusandhan Bhavan, 2 Rafi Marg, New Delhi, 110001, India. iakhan@iiim.res.in.
authors.forename: Inshad Ali
authors.initials: IA
authors.lastname: Khan
mesh_terms: D000995:Antitubercular Agents / Q000302:isolation & purification / Q000494:pharmacology*; D024901:Drug Resistance, Multiple, Bacterial; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015723:Gene Library; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000302:isolation & purification* / Q000378:metabolism; D012293:Rifampin / Q000494:pharmacology
chemical_list: D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D017853:Phosphotransferases (Alcohol Group Acceptor); C022642:shikimate kinase; D012293:Rifampin
keywords: Antitubercular; ChemBridge; Docking; Mycobacterium tuberculosis; Shikimate kinase