Small-molecule inhibitors specifically targeting type III secretion
Small-molecule inhibitors specifically targeting type III secretion
复制标题
DOI：
10.1128/iai.73.5.3104-3114.2005
复制
发表时间：
2005-05-01
影响因子：
3.1
通讯作者：
Elofsson, M
中科院分区：
文献类型：
--
作者：
Nordfelth, R;Kauppi, AM;Elofsson, M
III型分泌（TTS）系统被几种动物和植物病原体用于将效应蛋白递送到真核靶细胞的胞质溶胶中，作为逃避由感染的生物体引起的防御反应的策略。这些系统高度同源的事实意味着可以鉴定通过与III型分泌机制的特异性相互作用化学减弱病原体的新型抗菌剂。最近已经鉴定出许多具有这种潜力的小有机分子（A. M.考伊河Nordfelth，H. Uvell，H. Wolf-Watz和M. Elofsson，Chem.Biol.10：241-249，2003）。使用不同的报告基因构建体，我们表明，属于一类不同水杨醛酰化腙的化合物靶向假结核耶尔森氏菌的TTS系统。对这些化合物之一化合物1进行了详细研究，发现其在体外条件下通过靶向TTS系统特异性阻断Yop效应子分泌。在这方面，该药物模拟了钙对Yop分泌的众所周知的作用。此外，化合物I在感染HeLa细胞后抑制Yop效应子易位，而不影响真核细胞或细菌。模拟体内条件的HeLa细胞模型显示，化合物1化学上减弱病原体，从而有利于真核细胞。因此，我们的结果显示了概念的证明，即，靶向TTS系统的小化合物可以被鉴定出来，并且他们指出TTS抑制剂作为一类新型抗菌剂的可能用途。
The type III secretion (TTS) system is used by several animal and plant pathogens to deliver effector proteins into the cytosol of the eukaryotic target cell as a strategy to evade the defense reactions elicited by the infected organism. The fact that these systems are highly homologous implies that novel antibacterial agents that chemically attenuate the pathogens via a specific interaction with the type III secretion mechanism can be identified. A number of small organic molecules having this potential have recently been identified (A. M. Kauppi, R. Nordfelth, H. Uvell, H. Wolf-Watz, and M. Elofsson, Chem. Biol. 10:241-249, 2003). Using different reporter gene constructs, we showed that compounds that belong to a class of acylated hydrazones of different salicylaldehydes target the TTS system of Yersinia pseudotuberculosis. One of these compounds, compound 1, was studied in detail and was found to specifically block Yop effector secretion under in vitro conditions by targeting the TTS system. In this respect the drug mimics the well-known effect of calcium on Yop secretion. In addition, compound I inhibits Yop effector translocation after infection of HeLa cells without affecting the eukaryotic cells or the bacteria. A HeLa cell model that mimics in vivo conditions showed that compound 1 chemically attenuates the pathogen to the advantage of the eukaryotic cell. Thus, our results show proof of concept, i.e., that small compounds targeting the TTS system can be identified, and they point to the possible use of TTS inhibitors as a novel class of antibacterial agents.