Novel antibacterial agents derived from natural products

源自天然产物的新型抗菌剂

• 批准号: 9046851
• 负责人: Nigel D PRIESTLEY
• 金额: $ 29.57万
• 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 2018-07-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9046851
• 关键词: Address; Animals; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Bacillus anthracis; Biological Assay; Biological Availability; Cell Line; Communicable Diseases; Data; Development; Drops; Drug Design; Drug Kinetics; Drug Targeting; Effectiveness; Enterococcus faecalis; Evaluation; Event; Future; Genetic; Goals; Hand; Hour; Infection; Knowledge; Lead; Mammalian Cell; Maximum Tolerated Dose; Measures; Metabolic; Metabolism; Modeling; Modification; Molecular Target; Mus; Natural Products; Natural Products Chemistry; Oral; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Plasma; Property; Public Health; Resistance; Resistance profile; Small Business Innovation Research Grant; Staphylococcus aureus; Staphylococcus epidermidis; Streptococcus pyogenes; Structure; Thigh structure; Tracer; Validation; Vancomycin-resistant S. aureus; Work; analog; bacterial resistance; bactericide; base; cellular targeting; clinically relevant; drug development; evaluation/testing; improved; methicillin resistant Staphylococcus aureus; mouse model; mutant; novel; pathogen; public health relevance; resistance frequency

 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.

 描述（由适用提供）：常见细菌病原体中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。缺乏发现新抗生素的发现，尤其是那些具有新颖的作用机理的抗生素，抗药性问题更加复杂。由于对最近开发的抗生素的耐药性正在增长，因此需要新的抗生素。该项目的目的是发展我们 由我们的铅化合物PBI31G12举例说明的三唑诺甲酸酯抗生素是对革兰氏阳性病原体有效的宽光谱剂。具体而言，我们将改善当前铅化合物对金黄色葡萄球菌（包括MRSA），E. faecalis（包括VRE）和伪链球菌的抗菌活性和选择性。我们将获得有关三唑诺甲酸化合物化合物类MOA的假设，并确定目标，以便我们可以采用基于结构的药物设计来实现我们的效力和活动范围的目标。除了使用经典示踪剂研究，我们还将使用几种抗性 手中的细菌菌株以确定导致抗性的遗传修饰。除了提高效力和鉴定细胞靶标，我们还将启动DMPK研究，以确定三唑诺甲酸酯化合物类别是否具有任何关键责任，例如代谢不稳定性，耐药性差或靶标药理学。我们将确定化合物类别的最大耐受剂量和碱性药效特性（CMAX，AUC，T1/2，口服生物利用度）。然后，我们将评估最佳化合物在鼠S.金黄色葡萄球菌感染模型中是否显示出有效性。总而言之，该阶段I项目旨在获取具有提高效力和选择性，确定作用机理并评估DMPK属性的铅化合物的类似物。我们设想了一个II期项目，在该项目中，我们充分解决了ADMET问题和大量扩展动物研究，其改进的化合物设置将我们的化合物类别转移到我们最终的IND归档目标。