Lassomycin, a ribosomally synthesized cyclic peptide, kills mycobacterium tuberculosis by targeting the ATP-dependent protease ClpC1P1P2.
Lassomycin, a ribosomally synthesized cyclic peptide, kills mycobacterium tuberculosis by targeting the ATP-dependent protease ClpC1P1P2.
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DOI：
10.1016/j.chembiol.2014.01.014
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发表时间：
2014-04-24
影响因子：
--
通讯作者：
Lewis K
中科院分区：
文献类型：
--
作者：
Gavrish E;Sit CS;Cao S;Kandror O;Spoering A;Peoples A;Ling L;Fetterman A;Hughes D;Bissell A;Torrey H;Akopian T;Mueller A;Epstein S;Goldberg A;Clardy J;Lewis K
抗生素发现的减少和抗生素耐药性的蓬勃发展促进了抗生素发现的替代未开发来源的开发，包括以前未培养的细菌。在这里，我们筛选提取物从未培养的物种对M。并确定拉索霉素，一种抗生素，对生长和休眠的分枝杆菌，包括耐药形式的分枝杆菌表现出有效的杀菌活性。结核病，但对其他细菌或哺乳动物细胞几乎没有活性。拉索霉素是一种高度碱性的核糖体编码的环状肽，具有不寻常的结构折叠，仅部分类似于其他套索肽。我们表明，拉索霉素结合到一个高度酸性的区域的ClpC1 ATP酶复合物，并显着刺激其ATP酶活性，而不刺激ClpP1P2催化的蛋白质分解，这是必不可少的分枝杆菌的生存能力。这种机制，解偶联ATP酶从蛋白水解活性，占拉索霉素的杀菌活性。
Languishing antibiotic discovery and flourishing antibiotic resistance have prompted development of alternative untapped sources for antibiotic discovery, including previously uncultured bacteria. Here, we screen extracts from uncultured species against M. tuberculosis and identify lassomycin, an antibiotic that exhibits potent bactericidal activity against both growing and dormant mycobacteria, including drug-resistant forms of M. tuberculosis, but little activity against other bacteria or mammalian cells. Lassomycin is a highly basic, ribosomally-encoded cyclic peptide with an unusual structural fold that only partially resembles that of other lasso peptides. We show that lassomycin binds to a highly acidic region of the ClpC1 ATPase complex and markedly stimulates its ATPase activity without stimulating ClpP1P2 catalyzed protein breakdown, which is essential for viability of mycobacteria. This mechanism, uncoupling ATPase from proteolytic activity, accounts for lassomycin's bacteriocidal activity.
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影响因子：
6.4
作者：
Keren I;Minami S;Rubin E;Lewis K
通讯作者：
Lewis K
影响因子：
3
作者：
Morris, Garrett M.;Huey, Ruth;Lindstrom, William;Sanner, Michel F.;Belew, Richard K.;Goodsell, David S.;Olson, Arthur J.
通讯作者：
Olson, Arthur J.
DOI：
10.1107/s0907444909042073
发表时间：
2010-01
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Chen VB;Arendall WB 3rd;Headd JJ;Keedy DA;Immormino RM;Kapral GJ;Murray LW;Richardson JS;Richardson DC
通讯作者：
Richardson DC
影响因子：
15
作者：
Iwatsuki, Masato;Tomoda, Hiroshi;Omura, Satoshi
通讯作者：
Omura, Satoshi
影响因子：
4.4
作者：
Buerger, S.;Spoering, A.;Epstein, S. S.
通讯作者：
Epstein, S. S.