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（由申请人提供）：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，因为它损害了我们治疗传染病的能力。由于缺乏新抗生素的发现，特别是那些具有新作用机制的抗生素，使耐药性问题更加复杂。由于对最近开发的抗生素的耐药性正在增长，因此迫切需要新的抗生素。该项目的目标是开发我们的 三唑酮乳酸抗生素，如我们的先导化合物PBI 31 G12所例示，作为对革兰氏阳性病原体有活性的广谱剂。具体而言，我们将提高我们目前的先导化合物对S的抗菌活性和选择性。aureus（包括MRSA）、E. faecalis（包括VRE）和S.化脓我们将获得的数据，将使我们能够作出关于三唑酮乳酸化合物类的MOA的假设，并确定目标，使我们可以采用基于结构的药物设计，以实现我们的目标的效力和活性谱。除了使用经典的示踪剂研究，我们将使用几种耐药的 细菌菌株，以确定导致耐药性的遗传修饰。除了提高效力和鉴定细胞靶点之外，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缺陷，如代谢不稳定性、耐药性差或脱靶药理学。我们将确定化合物类别的最大耐受剂量和基本药效学特性（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S。金黄色葡萄球菌感染模型。总之，这个I期项目旨在获得我们的先导化合物的类似物，这些类似物具有改善的效力和选择性，确定作用机制并评估DMPK特性。我们设想了一个II期项目，其中我们完全解决ADMET问题，并大大扩展了动物研究与改进的化合物集，以移动我们的化合物类，我们的IND申请的最终目标。