Defining the mode of action of tetramic acid antibacterials derived from Pseudomonas aeruginosa quorum sensing signals.
Defining the mode of action of tetramic acid antibacterials derived from Pseudomonas aeruginosa quorum sensing signals.
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定义源自铜绿假单胞菌群体传感信号的四酸抗菌物的作用方式。
DOI：
10.1021/ja9056079
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发表时间：
2009-10-14
影响因子：
15
通讯作者：
Janda, Kim D.
中科院分区：
文献类型：
--
作者：
Lowery, Colin A.;Park, Junguk;Gloeckner, Christian;Meijler, Michael M.;Mueller, Ryan S.;Boshoff, Helena I.;Ulrich, Ricky L.;Barry, Clifton E., III;Bartlett, Douglas H.;Kravchenko, Vladimir V.;Kaufmann, Gunnar F.;Janda, Kim D.
在自然界中，细菌很少以单一、孤立的实体存在，而是作为由许多其他物种组成的群落，包括高等宿主生物。为了在这些竞争环境中生存，微生物制定了精心设计的策略，例如生物膜的形成和抗菌毒素的产生。最近，发现革兰氏阴性细菌铜绿假单胞菌（Pseudomonasaeruginosa）（一种机会性人类病原体）产生抗生素3-（1-羟基癸亚基）-5-（2-羟乙基）吡咯烷-2，4-二酮（C12-TA），其来源于其群体感应分子之一。在这里，我们提出了一个全面的研究C12-TA抗菌活性的扩展谱对铜绿假单胞菌在自然界中遇到的微生物竞争对手，以及显着的人类病原体。C12-TA的作用机制也被阐明，并发现C12-TA耗散革兰氏阳性菌的膜电位和pH梯度，与细胞死亡相关。值得注意的是，与其母体分子3-氧代-十二烷酰基高丝氨酸内酯（3-氧代-C12-HSL）形成鲜明对比，在用C12-TA处理的人细胞中既没有观察到细胞应激途径的活化也没有观察到细胞毒性。我们的研究结果表明，铜绿假单胞菌的QS机制已经进化为双重功能，既可以向同一物种的其他生物发出信号，也可以防御宿主免疫和竞争细菌。由于广谱抗菌活性、既定的作用模式、缺乏快速的耐药性发展以及人体细胞的耐受性，C12-TA支架也可以作为开发抗菌治疗剂的新的先导化合物。
In Nature, bacteria rarely exist as single, isolated entities, but rather as communities comprised of many other species including higher host organisms. To survive in these competitive environments, microorganisms have developed elaborate tactics such as the formation of biofilms and the production of antimicrobial toxins. Recently, it was discovered that the Gram-negative bacterium Pseudomonas aeruginosa, an opportunistic human pathogen, produces an antibiotic, 3-(1-hydroxydecylidene)-5-(2-hydroxyethyl)pyrrolidine-2,4-dione (C12-TA), derived from one of its quorum sensing molecules. Here, we present a comprehensive study of the expanded spectrum of C12-TA antibacterial activity against microbial competitors encountered by P. aeruginosa in Nature as well as significant human pathogens. The mechanism of action of C12-TA was also elucidated and C12-TA was found to dissipate both the membrane potential and pH gradient of Gram-positive bacteria, correlating well with cell death. Notably, in stark contrast to its parent molecule 3-oxo-dodecanoyl homoserine lactone (3-oxo-C12-HSL), neither activation of cellular stress pathways nor cytotoxicity was observed in human cells treated with C12-TA. Our results suggest that the QS machinery of P. aeruginosa has evolved for a dual-function, both to signal others of the same species, and also to defend against both host immunity and competing bacteria. Because of the broad-spectrum antibacterial activity, established mode of action, lack of rapid resistance development, and tolerance by human cells, the C12-TA scaffold may also serve as a new lead compound for the development of antimicrobial therapeutics.
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影响因子：
3.2
作者：
Chatterjee, A;Chaudhuri, S;Chowdhury, R
通讯作者：
Chowdhury, R
影响因子：
56.9
作者：
Kravchenko, Vladimir V.;Kaufmann, Gunnar F.;Ulevitch, Richard J.
通讯作者：
Ulevitch, Richard J.
影响因子：
3.2
作者：
Cabrol, SN;Olliver, A;Ruimy, R
通讯作者：
Ruimy, R
影响因子：
4.2
作者：
Favre-Bonté S;Chamot E;Köhler T;Romand JA;van Delden C
通讯作者：
van Delden C
影响因子：
4.4
作者：
Breeuwer, P;Drocourt, JL;Abee, T
通讯作者：
Abee, T