Targeting bacterial phosphatases for novel anti-bacterial agents.

描述（由申请人提供）：鼠疫耶尔森氏菌，肠沙门氏菌和小肠结肠炎耶尔森氏菌使用许多毒素来逃避免疫系统，其中一种是蛋白酪氨酸磷酸酶YopH。感染后，将YopH注射到吞噬细胞中，导致局灶黏附被破坏，并抑制整合素介导的细菌吞噬，这两者都高度依赖于酪氨酸磷酸化。因此，针对这些病原体的YopH是开发新型抗生素抗菌佐剂的一种明智但尚未充分探索的策略。我们的假设是，有效的小分子YopH抑制剂会使YopH瘫痪的免疫细胞立即恢复功能，从而能够启动先天和适应性免疫反应。因此，从这项初步研究中产生的分子可能非常有用，不仅作为潜在的治疗药物，而且在细胞水平上探索毒素诱导细胞死亡和抑制吞噬的机制，这是其他几种病原体所共有的。

DESCRIPTION (provided by applicant): Yersinia pestis, Salmonella enterica, and Yersinia enterocolitica use a number of toxins to evade the immune system one of which is the protein tyrosine phosphatase YopH. Following infection, YopH is injected into phagocytic cell resulting in the disruption of focal adhesions, and inhibition of integrin-mediated bacterial phagocytosis, both of which are highly dependent on tyrosine phosphorylation. Hence, targeting YopH against these pathogens represents a sensible yet underexplored strategy for the development of novel anti-bacterial adjuvant to antibiotics. Our hypothesis is that effective small-molecule inhibitors f YopH would render YopH- paralyzed immune cells immediately functional again hence able to initiate both innate and adaptive immune responses. Hence, the molecules that will arise from this pilot study may result very useful not only as potential therapeutics, but also in probing at the cellular level the mechanisms of toxin induced cell death and inhibition of phagocytosis, common to several other pathogens.