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 普通细菌病原体中抗生素抗性是一个严重的公共卫生问题 损害了我们治疗传染病的能力。抵抗问题是由于相对缺乏的复杂 发现新抗生素，尤其是具有新型作用机理的抗生素。新抗生素非常重要 由于对最近开发的抗生素的耐药性正在增长所需。该项目的目的是发展我们 三氯苯甲酸抗生素，一种新型的化合物，作为活性剂 针对革兰氏阳性病原体，例如金黄色葡萄球菌。基于 我们阶段I sttr项目的成功，我们将寻求提高对重要的效力和选择性 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标 并且，在体外和体内DMPK分析之后，证明了小鼠感染模型的效率。数据 获得的将用于证明化合物类的潜力，其目标是合作/超越 与他人许可，以完成启用IND申请的启用工作。 特定的目标1铅复合改进和评估。我们已经证明我们可以合成 不同的三唑酮统一衍生物以及初步的SAR研究，我们提高了效力（MIC） 针对临床相关的病原体，左右为1-4 µg/ml的MIC值。在这些研究的鼓励下，我们 寻求通过其他合成和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。药物开发已得到充分的准备 对药物靶标的知识可用于了解SAR。我们将确定离散的分子靶标 我们的三唑酮甲酸抗菌抗菌剂法。我们将结合多种方法 三唑诺酮靶靶标和金黄色葡萄球菌三唑诺酮抗性的遗传分析的标记 突变体。 特定目标3复合评估程序。该项目的第三个目标包括所有所需的 用于复合评估的分析方法，从效力到事件的初始测量范围 在小鼠中性大腿伯恩模型中的效率证明。分析工作是结合完成的 通过对特定目标1的SAR研究，以使设计，合成和评估的迭代循环将导致 优化效力，选择性，缺乏靶标药理学，可药用性和体内效率的化合物。