Novel antibacterial agents derived from natural products

具体目标 常见细菌病原体的抗生素耐药性是一个严重的公共卫生问题， 会影响我们治疗传染病的能力抗药性问题由于相对缺乏 发现新的抗生素，特别是那些具有新作用机制的抗生素。新的抗生素是关键 因为对最近开发的抗生素的耐药性正在增长。该项目的目标是开发我们的 三唑酮乳酸盐抗生素，一种新的结构类型的化合物，作为广谱活性剂 抗革兰氏阳性病原体，如耐甲氧西林金黄色葡萄球菌。基于 我们的第一阶段STTR项目的成功，我们将寻求提高效力和选择性对重要的 病原体，识别和验证我们的抗生素发挥其杀菌活性的分子靶点 并且在体外和体内DMPK分析后，在感染的小鼠模型中证明功效。数据 获得的将被用来证明复合类的潜力，其目标将是合作伙伴/出- 与他人合作完成IND申请的启动工作。 具体目标1领导化合物的改进和评价。我们已经证明我们可以合成 不同的三唑酮乳酸衍生物，并通过初步的SAR研究，我们已经提高了效力（MIC） 对临床相关病原体的MIC值约为1-4 µg/mL。在受到这些研究的鼓舞的同时， 寻求通过额外的合成和SAR研究进一步提高效力和选择性。 具体目标2目标识别和验证。药物开发已经得到了极大的促进， 药物靶点的知识可用于理解SAR。我们将确定离散分子目标 我们的三唑酮乳酸盐抗菌剂的作用。我们将结合使用光亲和性 三唑酮乳酸靶标的标记及S.金黄色葡萄球菌耐三唑酮乳酸菌 变种人 具体目标3化合物评价程序。该项目的第三个目标包括所有必要的 用于化合物评价的分析方法，从最初的效价测量到最终的 在小鼠贫血大腿负荷模型中证明功效。分析工作是结合 与具体目标1的SAR研究相结合，以便设计、综合和评估的迭代周期将导致 针对效力、选择性、缺乏脱靶药理学、可药用性和体内功效而优化的化合物。

SPECIFIC AIMS 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 relative 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, a novel structural class of compound, as broad spectrum agents active against Gram positive pathogens such as methicillin-resistant Staphylococcus aureus. Based on the success of our Phase I STTR project we will seek to improve both potency and selectivity against important pathogens, identify and validate the molecular target through which our antibiotics exert their bactericidal activity and, after in vitro and in vivo DMPK analysis, demonstrate efficacy in a mouse model of infection. The data obtained will be used to demonstrate the potential of the compound class, the goal of which will be to partner/out- license with others to complete the enabling work for the filing of an IND application. Specific Aim 1 Lead compound improvement and evaluation. We have demonstrated that we can synthesize diverse triazolononactate derivatives and through preliminary SAR studies we have improved the potency (MIC) against clinically relevant pathogens to around MIC values of 1-4 µg/mL. While encouraged by these studies we seek to further improve potency and selectivity through additional synthesis and SAR studies. Specific Aim 2 Target identification and validation. Drug development has been greatly facilitated where knowledge of the drug target can be used to understand SAR. We will determine the discrete molecular target at which our triazolononactate antibacterial agents act. We will use a combination of approaches photoaffinity labeling of the triazolononactate target and the genetic analysis of S. aureus triazolononactate resistance mutants. Specific Aim 3 Compound evaluation procedures. The third aim of this project encompasses all the required analytical methods for compound evaluation, ranging from initial measures of potency through to eventual demonstration of efficacy in a mouse neutropenic thigh burden model. The analytical work is done in conjunction with the SAR studies of specific aim 1 so that iterative cycles of design, synthesis and evaluation will lead to a compound optimized for potency, selectivity, lack of off-target pharmacology, druggability and in vivo efficacy.