Antibiotic acyldepsipeptides activate ClpP peptidase to degrade the cell division protein FtsZ
Antibiotic acyldepsipeptides activate ClpP peptidase to degrade the cell division protein FtsZ
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DOI：
10.1073/pnas.1110385108
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发表时间：
2011-10-18
影响因子：
11.1
通讯作者：
Broetz-Oesterhelt, Heike
中科院分区：
文献类型：
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作者：
Sass, Peter;Josten, Michaele;Broetz-Oesterhelt, Heike
抗生素耐药细菌在全球范围内的传播，迫切需要寻找具有新作用模式的抗生素，这些抗生素没有预先存在的交叉耐药性。我们先前描述了一类独特的酰基缩酚酸肽（ADEP），其对革兰氏阳性病原体（包括链球菌、肠球菌以及多重耐药金黄色葡萄球菌）具有显著的抗菌活性。在这里，我们报告说，ADEP阻止革兰氏阳性菌的细胞分裂，并诱导杆状枯草芽孢杆菌的强烈抑制和球状S。金黄色葡萄球菌和肺炎链球菌。它出现的ADEP治疗抑制隔膜形成的阶段，Z-环组装，和中央细胞分裂蛋白从中间细胞的位置离域。使用在体内和体外的研究，我们表明，抑制Z-环的形成是一个结果的蛋白水解降解的基本细胞分裂蛋白FtsZ。ADEP将细菌ClpP肽酶从受调节的蛋白酶转变为不受控制的蛋白酶，并且事实证明FtsZ特别容易被ADEP-ClpP复合物降解。通过阻止细胞分裂，ADEP抑制了细菌的一个重要细胞过程，到目前为止，任何治疗应用的抗生素都没有针对该过程。其独特的多方面作用机制和抗菌效力使其成为未来抗生素开发的有希望的领导结构。
The worldwide spread of antibiotic-resistant bacteria has lent urgency to the search for antibiotics with new modes of action that are devoid of preexisting cross-resistances. We previously described a unique class of acyldepsipeptides (ADEPs) that exerts prominent antibacterial activity against Gram-positive pathogens including streptococci, enterococci, as well as multidrug-resistant Staphylococcus aureus. Here, we report that ADEP prevents cell division in Gram-positive bacteria and induces strong filamentation of rod-shaped Bacillus subtilis and swelling of coccoid S. aureus and Streptococcus pneumoniae. It emerged that ADEP treatment inhibits septum formation at the stage of Z-ring assembly, and that central cell division proteins delocalize from midcell positions. Using in vivo and in vitro studies, we show that the inhibition of Z-ring formation is a consequence of the proteolytic degradation of the essential cell division protein FtsZ. ADEP switches the bacterial ClpP peptidase from a regulated to an uncontrolled protease, and it turned out that FtsZ is particularly prone to degradation by the ADEP-ClpP complex. By preventing cell division, ADEP inhibits a vital cellular process of bacteria that is not targeted by any therapeutically applied antibiotic so far. Their unique multifaceted mechanism of action and antibacterial potency makes them promising lead structures for future antibiotic development.