title: Identification of shikimate kinase inhibitors among anti-Mycobacterium tuberculosis compounds by LC-MS.
abstract: Increasing drug resistance has challenged the control and treatment of tuberculosis, sparking recent interest in finding new antitubercular agents with different chemical scaffolds and mechanisms of action. Mycobacterium tuberculosis shikimate kinase (MtSK), an enzyme present in the shikimate pathway in bacteria, is essential for the survival of the tubercle bacillus, representing an ideal target for therapeutic intervention given its absence in mammals. In this study, a small library of 404 synthetic antimycobacterial compounds identified and supplied through the NIH Tuberculosis Antimicrobial Acquisition and Coordinating Facility (TAACF) high throughput screening program against whole cell M. tuberculosis H37Rv was further screened using a mass spectrometry-based functional assay in order to identify a potential enzymatic target. Fourteen compounds containing an oxadiazole-amide or a 2-aminobenzothiazole core scaffold showed MtSK inhibitory activity at 50 μM, with the lowest giving an IC50 of 1.94 μM. Induced fit docking studies suggested that the scaffolds shared by these compounds fit well in the shikimate binding pocket of MtSK. In summary, we report new early discovery stage lead scaffolds targeting the essential protein MtSK that can be further pursued in a rational drug design program for the discovery of more selective antitubercular drugs.
authors.affiliation: Department of Pharmacal Sciences, Harrison School of Pharmacy, 4306 Walker Building, Auburn University, Auburn, AL 36849, USA.
authors.forename: Johayra
authors.initials: J
authors.lastname: Simithy
authors.affiliation: Department of Pharmacal Sciences, Harrison School of Pharmacy, 4306 Walker Building, Auburn University, Auburn, AL 36849, USA.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Reeve
authors.affiliation: Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35205, USA.
authors.forename: Judith V
authors.initials: JV
authors.lastname: Hobrath
authors.affiliation: University of Alabama at Birmingham, Department of Chemistry, 1530 3rd Avenue South, Birmingham, AL 35294, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Reynolds
authors.affiliation: Department of Pharmacal Sciences, Harrison School of Pharmacy, 4306 Walker Building, Auburn University, Auburn, AL 36849, USA. Electronic address: aic0001@auburn.edu.
authors.forename: Angela I
authors.initials: AI
authors.lastname: Calderón
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D002853:Chromatography, Liquid; D015195:Drug Design; D004352:Drug Resistance, Microbial; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D006867:Hydrolases / Q000187:drug effects*; D008297:Male; D013058:Mass Spectrometry; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D012765:Shikimic Acid / Q000494:pharmacology*; D015398:Signal Transduction; D014376:Tuberculosis / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology
chemical_list: D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D012765:Shikimic Acid; D017853:Phosphotransferases (Alcohol Group Acceptor); C022642:shikimate kinase; D006867:Hydrolases; C527647:HsaD protein, Mycobacterium tuberculosis
keywords: LC-MS; Mycobacterium tuberculosis; Shikimate kinase; Shikimate-3-phosphate