Dysregulation of bacterial proteolytic machinery by a new class of antibiotics
Dysregulation of bacterial proteolytic machinery by a new class of antibiotics
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DOI：
10.1038/nm1306
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发表时间：
2005-10-01
期刊：
影响因子：
82.9
通讯作者：
Labischinski, H
中科院分区：
文献类型：
--
作者：
Brötz-Oesterhelt, H;Beyer, D;Labischinski, H
在这里，我们表明，一类新的抗生素-酰基缩酚酸肽-具有抗菌活性，对革兰氏阳性菌在体外和几种啮齿动物模型的细菌感染。酰基缩酚肽对临床应用中对抗生素耐药的分离株具有活性，这意味着一个新的靶标，我们将其鉴定为ClpP，主要细菌蛋白酶复合物的核心单元。ClpP通常受到严格调节，并且严格需要Clp-ATP酶家族的成员以及通常进一步的辅助蛋白来进行蛋白水解激活。酰基缩酚肽与ClpP的结合消除了这些保护措施。酰基缩酚酸肽激活的ClpP核心能够在不存在调节Clp-ATP酶的情况下进行蛋白水解降解。这种不受控制的蛋白水解导致细菌细胞分裂的抑制并最终导致细胞死亡。
Here we show that a new class of antibiotics-acyldepsipeptides-has antibacterial activity against Gram-positive bacteria in vitro and in several rodent models of bacterial infection. The acyldepsipeptides are active against isolates that are resistant to antibiotics in clinical application, implying a new target, which we identify as ClpP, the core unit of a major bacterial protease complex. ClpP is usually tightly regulated and strictly requires a member of the family of Clp-ATPases and often further accessory proteins for proteolytic activation. Binding of acyldepsipeptides to ClpP eliminates these safeguards. The acyldepsipeptide-activated ClpP core is capable of proteolytic degradation in the absence of the regulatory Clp-ATPases. Such uncontrolled proteolysis leads to inhibition of bacterial cell division and eventually cell death.