Antitubercular specific activity of ibuprofen and the other 2-arylpropanoic acids using the HT-SPOTi whole-cell phenotypic assay.
Antitubercular specific activity of ibuprofen and the other 2-arylpropanoic acids using the HT-SPOTi whole-cell phenotypic assay.
复制标题
使用 HT-SPOTi 全细胞表型测定测定布洛芬和其他 2-芳基丙酸的抗结核比活性。
DOI：
10.1136/bmjopen-2013-002672
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发表时间：
2013-06-20
期刊：
影响因子：
2.9
通讯作者：
Bhakta S
中科院分区：
文献类型：
--
作者：
Guzman JD;Evangelopoulos D;Gupta A;Birchall K;Mwaigwisya S;Saxty B;McHugh TD;Gibbons S;Malkinson J;Bhakta S
迫切需要具有新型作用机制的抗结核先导分子来推动抗结核药物的发现。本研究的目的是验证利用高通量斑点培养生长抑制（HT-SPOTi）法筛选抗结核分枝杆菌化合物文库的可行性，并研究布洛芬（IBP）和其他2-芳基丙酸对结核分枝杆菌和其他分枝杆菌的生长抑制作用。HT-SPOTi方法不仅用已知药物进行了验证，而且还用ChEMBL数据库中发表的47种已证实的抗结核活性化合物进行了验证。三种非处方非甾体抗炎药也包括在筛查中。包括IBP在内的2-芳基丙酸对不同分枝杆菌菌株的表型和生理作用进行了综合评价，并测定了它们对小鼠RAW264.7巨噬细胞的细胞毒性。此外，采用比较生物信息学分析提出了一个潜在的分枝杆菌靶点。IBP具有抗结核作用，而卡洛芬是2-芳基丙烷类药物中最有效的。发现3,5-二硝基IBP衍生物比IBP更有效，但同样具有选择性。IBP的其他合成衍生物活性较低，IBP的游离羧酸似乎是其抗结核活性所必需的。IBP、卡洛芬和3,5-二硝基IBP衍生物对多药耐药分离株和固定相杆菌具有活性。在2-芳基丙烷类镇痛药的人体靶点基础上，提出结核分枝杆菌蛋白起始因子infB （Rv2839c）作为潜在的分子靶点。该方法可靠、重复性好，可用于筛选不同化合物的抑菌效价。IBP表现出特异性的抗结核活性，而卡洛芬是2-芳基丙烷类药物中选择性最强的药物。对固定相杆菌和多重耐药分离株的活性使我们推测出一种新的抗真菌作用机制。进一步的药物化学和靶点阐明研究可能会带来新的结核病治疗方法。
Lead antituberculosis (anti-TB) molecules with novel mechanisms of action are urgently required to fuel the anti-TB drug discovery pipeline. The aim of this study was to validate the use of the high-throughput spot culture growth inhibition (HT-SPOTi) assay for screening libraries of compounds against Mycobacterium tuberculosis and to study the inhibitory effect of ibuprofen (IBP) and the other 2-arylpropanoic acids on the growth inhibition of M tuberculosis and other mycobacterial species. The HT-SPOTi method was validated not only with known drugs but also with a library of 47 confirmed anti-TB active compounds published in the ChEMBL database. Three over-the-counter non-steroidal anti-inflammatory drugs were also included in the screening. The 2-arylpropanoic acids, including IBP, were comprehensively evaluated against phenotypically and physiologically different strains of mycobacteria, and their cytotoxicity was determined against murine RAW264.7 macrophages. Furthermore, a comparative bioinformatic analysis was employed to propose a potential mycobacterial target. IBP showed antitubercular properties while carprofen was the most potent among the 2-arylpropanoic class. A 3,5-dinitro-IBP derivative was found to be more potent than IBP but equally selective. Other synthetic derivatives of IBP were less active, and the free carboxylic acid of IBP seems to be essential for its anti-TB activity. IBP, carprofen and the 3,5-dinitro-IBP derivative exhibited activity against multidrug-resistant isolates and stationary phase bacilli. On the basis of the human targets of the 2-arylpropanoic analgesics, the protein initiation factor infB (Rv2839c) of M tuberculosis was proposed as a potential molecular target. The HT-SPOTi method can be employed reliably and reproducibly to screen the antimicrobial potency of different compounds. IBP demonstrated specific antitubercular activity, while carprofen was the most selective agent among the 2-arylpropanoic class. Activity against stationary phase bacilli and multidrug-resistant isolates permits us to speculate a novel mechanism of antimycobacterial action. Further medicinal chemistry and target elucidation studies could potentially lead to new therapies against TB.
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DOI：
10.1073/pnas.1214188109
发表时间：
2012-10-02
影响因子：
11.1
作者：
Gold, Ben;Pingle, Maneesh;Nathan, Carl F.
通讯作者：
Nathan, Carl F.
影响因子：
3.2
作者：
Lew, Jocelyne M.;Kapopoulou, Adamandia;Cole, Stewart T.
通讯作者：
Cole, Stewart T.
DOI：
10.1164/ajrccm.161.1.9902113
发表时间：
2000-01-01
影响因子：
24.7
作者：
Kuo, HP;Wang, CH;Lu, LC
通讯作者：
Lu, LC
芳基胺N-乙酰转移酶是牛肉杆菌BCG中合成霉菌酸和复杂脂质所必需的，它代表了一种新型的药物靶标。
影响因子：
15.3
作者：
Bhakta, S;Besra, GS;Upton, AM;Parish, T;Sholto-Douglas-Vernon, C;Gibson, KJC;Knutton, S;Gordon, S;daSilva, RP;Anderton, MC;Sim, E
通讯作者：
Sim, E
影响因子：
5.2
作者：
Guzman, Juan D.;Gupta, Antima;Bhakta, Sanjib
通讯作者：
Bhakta, Sanjib