Antibacterial Therapy by Pathogen Osmolality Disruption

描述（由申请人提供）：最近的生物恐怖主义威胁加剧了对新型抗生素的需求。在生物防御A类细菌病原体中，许多物种目前对现有抗生素敏感。然而，发展对多种抗生素具有耐药性的炭疽芽孢杆菌和鼠疫耶尔森氏菌的生物武器菌株是一种明显的可能性。除了生物防御病原体清单上的病原体外，其他形式的细菌感染仍然是发病率和死亡率的常见原因。为了开始解决这些未满足的需求，我们提出了一项针对细菌机械敏感（MS）通道的重点研究。质谱通道使细菌能够迅速适应环境中的渗透变化。虽然不是必需的，但功能获得（GOF）突变可以组成性地激活质谱通道，具有杀菌作用。在该项目的初始阶段，我们将使用我们专有的Mpex微型电池技术来证明E. coil质谱通道的“可药物性”。Mpex微型细胞将实现高通量、小分子和天然产物筛选，以识别模拟致命GOF表型的化合物激活剂。结合这些研究，我们将验证来自炭疽杆菌和鼠疫杆菌的同源生物防御相关质谱通道的功能。利用E. coil和Mpex微型细胞，我们还将表征针对E. coil MS靶点鉴定的GOF调节剂对这些致病性MS通道蛋白的活性。因此，I期试验证明了将MS靶点和Mpex微型细胞一起用于有效鉴定新型抗菌先导物的概念，并提供了在各种生物防御a类致病物种中发现的MS同源物的进一步功能靶点验证。在I期成功验证后，II期研究将包括使用Mpex微型细胞筛选这些致病性MS同源物，优先选择命中，并优化先导物以产生ind候选分子。

DESCRIPTION (provided by applicant): The recent threat of bioterrorism has intensified the need for new classes of antibiotics. Among biodefense category A bacterial pathogens, many species are currently susceptible to existing antibiotics. However, the development of bioweapon strains of Bacillus anthracis and Yersinia pestis that are resistant to multiple antibiotics is a distinct possibility. In addition to agents present on the biodefense pathogen list, other forms of bacterial infections continue to be a common cause of morbidity and mortality. To begin addressing these unmet needs, we are proposing a focused study targeting bacterial mechanosensitive (MS) channels. MS channels enable bacteria to rapidly adapt to osmotic changes in their environment. Although non-essential, gain-of-function (GOF) mutations that constitutively activate MS channels are bactericidal. Over the initial phase of this project, we will demonstrate the "drugability" of the E. coil MS channel using our proprietary Mpex minicell technology. The Mpex minicell will enable high-throughput, small molecule and natural product screening to identify compound activators that mimic the lethal GOF phenotype. In conjunction with these studies, we will validate the function of homologous, biodefense-related MS channels from B. anthracis and Y. pestis. Using E. coil and Mpex minicells, we will also characterize the GOF modulators identified against the E. coil MS target for activity against these pathogenic MS channeling proteins. Thus, Phase I stands as a proof-of-concept for the use of the MS target and Mpex minicells together to effectively identify novel antibacterial leads, and provides in parallel further functional target validation of MS homologs found in various biodefense category A pathogenic species. Following successful validation in Phase I, Phase II studies will include screening of these pathogenic MS homologs using Mpex minicells, prioritization of hits, and lead optimization to produce an IND-enabling candidate molecule.