Novel antibacterial agents derived from natural products

源自天然产物的新型抗菌剂

基本信息

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
项目类别：
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

项目摘要

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。由于缺乏新的抗生素，特别是具有新作用机制的抗生素，耐药性问题变得更加复杂。由于对最近开发的抗生素的耐药性不断增加，迫切需要新的抗生素。该项目的目标是开发我们的抗生素。三唑酮壬酸抗生素，例如我们的先导化合物 PBI31G12，作为对革兰氏阳性病原体具有活性的广谱药物，我们将专门提高我们目前的先导化合物对金黄色葡萄球菌（包括 MRSA）、粪肠球菌（包括 VRE）的抗菌活性和选择性。）和化脓性链球菌，我们将获得数据，使我们能够对三唑酮壬酸化合物类的 MOA 做出假设并识别目标，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性谱目标。除了使用经典的示踪剂研究之外，我们还将使用几种耐药性。除了提高效力和识别细胞靶标外，我们还将启动 DMPK 研究，以确定三唑酮壬酸化合物类是否存在任何关键缺陷，例如代谢不稳定、耐药性差或关闭。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），然后评估我们的最佳化合物是否在小鼠金黄色葡萄球菌中显示出有效性。总之，该第一阶段项目旨在获得具有改进效力和选择性的先导化合物的类似物，确定作用机制并评估 DMPK 特性，因为我们完全解决了 ADMET 问题并评估了 DMPK 特性。通过改进的化合物组极大地扩展了动物研究，使我们的化合物类别实现了 IND 申请的最终目标。