Novel antibacterial agents derived from natural products

 描述(申请人提供)：常见细菌病原体之间的抗生素耐药性是一个严重的公共卫生问题，因为它损害了我们治疗传染病的能力。由于缺乏新的抗生素，特别是那些具有新作用机制的抗生素，耐药性问题变得更加复杂。随着对最近开发的抗生素的耐药性不断增长，迫切需要新的抗生素。这个项目的目标是发展我们的 三唑酮类抗生素，如我们的先导化合物PBI31G12，作为广谱制剂对革兰氏阳性病原体有效。具体地说，我们将提高目前先导化合物对金黄色葡萄球菌(包括MRSA)、粪肠球菌(包括VRE)和化脓性葡萄球菌的抗菌活性和选择性。我们将获得数据，这些数据将使我们能够对三唑酮类化合物的MOA做出假设，并确定目标，以便我们可以使用基于结构的药物设计来实现我们的效力和活性光谱目标。除了使用经典的示踪剂研究外，我们还将使用几种抗性 细菌菌株手中确定导致耐药性的基因修饰。除了效力的提高和细胞靶点的确定之外，我们还将启动DMPK研究，以确定三唑酮乳酸盐化合物类别是否具有任何关键的易感性，如代谢不稳定、不良的耐药性或偏离靶点的药理作用。我们将确定该化合物类的最大耐受量和基本药效学性质(Cmax、AUC、T1/2、口服生物利用度)。然后，我们将评估我们最好的化合物是否在小鼠金黄色葡萄球菌感染模型中显示出有效性。总而言之，这个第一阶段的项目寻求获得我们的先导化合物的类似物，这些化合物具有更好的效力和选择性，确定作用机制，并评估DMPK的性质。我们设想了一个第二阶段的项目，在这个项目中，我们完全解决了ADMET问题，并通过改进的化合物集极大地扩展了动物研究，将我们的化合物类转移到我们的最终目标IND备案。

 DESCRIPTION (provided by applicant): Antibiotic resistance among common bacterial pathogens is a serious public health problem as it compromises our ability to treat infectious disease. The resistance problem is compounded by the lack of discovery of new antibiotics, especially those with novel mechanisms of action. New antibiotics are critically needed as resistance to recently developed antibiotics is growing. The goal of this project is to develop our triazolononactate antibiotics, as exemplified by our lead compound PBI31G12, as broad spectrum agents active against Gram positive pathogens. Specifically we will improve the antibacterial activity and selectivity of our current lead compounds against S. aureus (including MRSA), E. faecalis (including VRE) and S. pyogenes. We will obtain data that will allow us to make a hypothesis concerning the MOA of the triazolononactate compound class and to identify the target so that we may employ structure-based drug design to achieve our goals of potency and spectrum of activity. In addition to using classic tracer studies we will use several resistant bacterial strains in hand to determine the genetic modifications leading to resistance. Beyond the improvement of potency and identification of the cellular target we will initiate DMPK studies to determine if the triazolononactate compound class has any critical liabilities such as metabolic instability, a poor resistance profile or off target pharmacology. We will determine the maximal tolerated dose and basic pharmacodynamic properties (Cmax, AUC, t1/2, oral bioavailability) of the compound class. We will then assess whether our best compounds show effectiveness in a murine S. aureus infection model. In summary, this Phase I project seeks to obtain analogs of our lead compound that have improved potency and selectivity, identify a mechanism of action and to evaluate DMPK properties. We envisage a Phase II project wherein we fully address ADMET issues and greatly expand animal studies with an improved compound set to move our compound class to our eventual goal of an IND filing.