Improved Phenoxyalkylbenzimidazoles with Activity against Mycobacterium tuberculosis Appear to Target QcrB.
Improved Phenoxyalkylbenzimidazoles with Activity against Mycobacterium tuberculosis Appear to Target QcrB.
复制标题
DOI：
10.1021/acsinfecdis.7b00112
复制
发表时间：
2017-12-08
影响因子：
5.3
通讯作者：
Parish T
中科院分区：
文献类型：
--
作者：
Chandrasekera NS;Berube BJ;Shetye G;Chettiar S;O'Malley T;Manning A;Flint L;Awasthi D;Ioerger TR;Sacchettini J;Masquelin T;Hipskind PA;Odingo J;Parish T
苯氧基烷基苯并咪唑具有良好的抗结核活性。我们扩展了我们的结构-活性关系研究，以确定活性所需的pab的核心成分。最有效的化合物对结核分枝杆菌的抑制浓度最低，在低纳摩尔范围内，对真核细胞的细胞毒性非常小，对细胞内细菌的活性也很小。我们分离出抗PAB化合物的耐药突变体，这些突变体在Rv1339（功能未知）或qcrB（电子传递链细胞色素bc1氧化酶的一个组成部分）中发生突变。QcrB突变株对所有PAB化合物都具有抗性，而Rv1339突变株仅对一个亚群具有抗性，表明QcrB是靶标。PAB化合物靶点的发现将允许改进设计靶向细胞内结核分枝杆菌的新化合物。
The phenoxy alkyl benzimidazoles (PABs) have good antitubercular activity. We expanded our structure–activity relationship studies to determine the core components of PABs required for activity. The most potent compounds had minimum inhibitory concentrations against Mycobacterium tuberculosis in the low nanomolar range with very little cytotoxicity against eukaryotic cells as well as activity against intracellular bacteria. We isolated resistant mutants against PAB compounds, which had mutations in either Rv1339, of unknown function, or qcrB, a component of the cytochrome bc1 oxidase of the electron transport chain. QcrB mutant strains were resistant to all PAB compounds, whereas Rv1339 mutant strains were only resistant to a subset, suggesting that QcrB is the target. The discovery of the target for PAB compounds will allow for the improved design of novel compounds to target intracellular M. tuberculosis.
登录
查看更多内容
影响因子：
4
作者：
Lambert, RJW;Pearson, J
通讯作者：
Pearson, J
影响因子：
4.9
作者：
Ortiz, Diana;Forquer, Isaac;Landfear, Scott M.
通讯作者：
Landfear, Scott M.
影响因子：
2.8
作者：
Gengenbacher, Martin;Rao, Srinivasa P. S.;Dick, Thomas
通讯作者：
Dick, Thomas
影响因子：
3.7
作者：
Darby CM;Ingólfsson HI;Jiang X;Shen C;Sun M;Zhao N;Burns K;Liu G;Ehrt S;Warren JD;Andersen OS;Brickner SJ;Nathan C
通讯作者：
Nathan C
影响因子：
5.2
作者：
Zelmer, Andrea;Carroll, Paul;Schaible, Ulrich E.
通讯作者：
Schaible, Ulrich E.