Inhibition of mycolic acid transport across the Mycobacterium tuberculosis plasma membrane.
Inhibition of mycolic acid transport across the Mycobacterium tuberculosis plasma membrane.
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DOI：
10.1038/nchembio.794
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发表时间：
2012-02-19
影响因子：
14.8
通讯作者：
Jackson, Mary
中科院分区：
文献类型：
--
作者：
Grzegorzewicz, Anna E.;Ha Pham;Gundi, Vijay A. K. B.;Scherman, Michael S.;North, Elton J.;Hess, Tamara;Jones, Victoria;Gruppo, Veronica;Born, Sarah E. M.;Kordulakova, Jana;Chavadi, Sivagami Sundaram;Morisseau, Christophe;Lenaerts, Anne J.;Lee, Richard E.;McNeil, Michael R.;Jackson, Mary
新的化疗药物对多药耐药结核分枝杆菌（M。TB是迫切需要的。我们报告的鉴定金刚烷基脲化合物显示出有效的杀菌活性对M。TB和一种独特的作用模式，即消除分枝菌酸从细胞质的易位，在细胞质中，分枝菌酸被合成到质膜的周质侧，在周质侧，分枝菌酸被转移到细胞壁阿拉伯半乳聚糖上或用于形成与毒性相关的外膜含海藻糖的糖脂。自发抗性突变体的全基因组测序。tb在体外选择，然后通过遗传验证实验表明，我们的原型抑制剂靶向内膜转运蛋白，MmpL3。在分枝杆菌中mmpL3的条件性基因表达和对经代谢物处理的细胞的分析验证了MmpL3对于分枝杆菌生长是必不可少的，并支持该转运蛋白参与海藻糖单分枝杆菌酸酯跨质膜的转运。
New chemotherapeutics active against multidrug-resistant Mycobacterium tuberculosis (M. tb) are urgently needed. We report on the identification of an adamantyl urea compound displaying potent bactericidal activity against M. tb and a unique mode of action, namely the abolition of the translocation of mycolic acids from the cytoplasm where they are synthesized to the periplasmic side of the plasma membrane where they are transferred onto cell wall arabinogalactan or used in the formation of virulence-associated outer membrane trehalose-containing glycolipids. Whole genome sequencing of spontaneous resistant mutants of M. tb selected in vitro followed by genetic validation experiments revealed that our prototype inhibitor targets the inner membrane transporter, MmpL3. Conditional gene expression of mmpL3 in mycobacteria and analysis of inhibitor-treated cells validate MmpL3 as essential for mycobacterial growth and support the involvement of this transporter in the translocation of trehalose monomycolate across the plasma membrane.
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影响因子：
4.8
作者：
Domenech, P;Reed, MB;Barry, CE
通讯作者：
Barry, CE
影响因子：
3.5
作者：
Brown, Joshua R.;North, Elton J.;Hurdle, Julian G.;Morisseau, Christophe;Scarborough, Jerrod S.;Sun, Dianqing;Kordulakova, Jana;Scherman, Michael S.;Jones, Victoria;Grzegorzewicz, Anna;Crew, Rebecca M.;Jackson, Mary;McNeil, Michael R.;Lee, Richard E.
通讯作者：
Lee, Richard E.
影响因子：
3.2
作者：
Guo, Xinzheng V.;Monteleone, Mercedes;Schnappinger, Dirk
通讯作者：
Schnappinger, Dirk
影响因子：
4.8
作者：
Korduláková, J;Gilleron, M;Jackson, M
通讯作者：
Jackson, M
DOI：
10.1385/1-59259-147-7:059
发表时间：
2001-01-01
期刊：
Methods in molecular medicine
影响因子：
--
作者：
Jackson, M;Reinaldo Camacho, L;Guilhot, C
通讯作者：
Guilhot, C