结核分枝杆菌
肺结核
莽草酸途径
抗细菌
化学
抗菌剂
海洋分枝杆菌
抗药性
酶
微生物学
组合化学
药理学
生物化学
生物
医学
芳香族氨基酸
病理
作者
Johayra Simithy,Nathaniel Reeve,Judith V. Hobrath,Robert C. Reynolds,Ángela I. Calderón
出处
期刊:Tuberculosis
[Elsevier]
日期:2014-03-01
卷期号:94 (2): 152-158
被引量:31
标识
DOI:10.1016/j.tube.2013.12.004
摘要
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.
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