Novel antibacterial agents derived from natural products

源自天然产物的新型抗菌剂

• 批准号: 9906163
• 负责人: Nigel D PRIESTLEY
• 金额: $ 75.04万
• 依托单位: PROMILIAD BIOPHARMA, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906163
• 关键词: Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Communicable Diseases; Data; Drug Targeting; Evaluation; Event; Goals; In Vitro; Infection; Knowledge; Lead; Licensing; Measures; Modeling; Molecular Target; Mus; Natural Products; Natural Products Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; Photoaffinity Labels; Procedures; Public Health; Resistance; Small Business Technology Transfer Research; Staphylococcus aureus; Structure; Thigh structure; Validation; Work; analytical method; bactericide; base; clinically relevant; design; drug development; genetic analysis; improved; in vivo; methicillin resistant Staphylococcus aureus; mouse model; mutant; novel; pathogen; pathogenic bacteria; success

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.

具体目标 常见细菌的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。阻力问题因相对缺乏而变得更加复杂 发现新的抗生素，特别是那些具有新作用机制的抗生素。新的抗生素至关重要 因为对最近开发的抗生素的抗药性正在增长。这个项目的目标是发展我们的 三唑酮类抗生素，一种新的结构类化合物，具有广谱活性 对抗革兰氏阳性病原体，如耐甲氧西林金黄色葡萄球菌。基于 我们第一阶段STTR项目的成功，我们将寻求提高效力和选择性，以应对重要的 病原体，识别和验证我们的抗生素发挥杀菌活性的分子靶点 并且，在体外和体内的DMPK分析之后，在小鼠感染模型中证明了有效性。数据 所获得的将用于展示复合类的潜力，其目标将是合作/输出- 向其他人发放许可证，以完成提交IND申请的启用工作。 具体目标1领导化合物改进和评估。我们已经证明了我们可以合成 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最低抑菌浓度约为1-4微克/毫升。虽然受到这些研究的鼓舞，但我们 寻求通过更多的合成和SAR研究进一步提高效力和选择性。 特定目标2目标识别和验证。药物开发在以下方面得到了极大的便利 药物靶点的知识可以用来理解合成孔径雷达。我们将确定离散的分子靶标 我们的三唑酮酸类抗菌剂在此起作用。我们将结合使用光亲和力的方法 三唑丙酮类靶标的标记及金黄色葡萄球菌耐药性的遗传分析 变种人。 具体目标3复合评价程序。该项目的第三个目标包括所有必需的 化合物评价的分析方法，从最初的效力测量到最终的 在小鼠中性粒细胞减少的大腿负荷模型中的有效性演示。分析工作是联合进行的 具有具体目标1的SAR研究，以便设计、综合和评估的迭代周期将导致 针对效力、选择性、缺乏非靶标药理作用、可药性和体内疗效而优化的化合物。