Targeting bacterial phosphatases for novel anti-bacterial agents.

描述(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，其中之一是蛋白酪氨酸磷酸酶YopH。感染后，YopH被注射到吞噬细胞中，导致局部黏附的破坏，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是一种明智但尚未被探索的策略，用于开发抗生素的新型抗菌佐剂。我们的假设是，有效的YopH小分子抑制剂将使YopH瘫痪的免疫细胞立即恢复功能，从而能够启动先天和获得性免疫反应。因此，从这项初步研究中产生的分子不仅可能作为潜在的治疗药物，而且还可能在细胞水平上探索毒素诱导细胞死亡和抑制吞噬作用的机制，这些机制与其他几种病原体一样。 公共卫生相关性：我们设想一种关键细菌毒素的抑制剂可能对治疗鼠疫耶尔森氏菌、肠炎沙门氏菌和小肠结肠炎耶尔森菌感染有价值， 作为抗生素的支持性补充。这项初步研究将为这一创新方法提供关键的概念证明。

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. PUBLIC HEALTH RELEVANCE: We envision that inhibitors of a critical bacterial toxin may be valuable for treating Yersinia pestis, Salmonella enterica, and Yersinia enterocolitica infections, as a supportive complement to antibiotics. This pilot study will provide critical proof of concept for this innovative approach.