Teixobactin Development for Anthrax

针对炭疽病的 Teixobactin 开发

• 批准号: 10192649
• 负责人: Dallas Hughes
• 金额: $ 99.64万
• 依托单位: NOVOBIOTIC PHARMACEUTICALS, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10192649
• 关键词: Acute; Animal Model; Animals; Anthrax disease; Antibiotic Therapy; Antibiotics; Bacillus anthracis; Binding; Binding Proteins; Bioreactors; Cell Count; Cell Wall; Cells; Clinical; Clinical Research; Clinical Trials; Contracts; Cyclic GMP; Development; Dose; Drug Kinetics; Drug resistance; Drug usage; Engineering; Evaluation; Exposure to; Fermentation; Funding; Future; Goals; Gram-Positive Bacteria; Grant; Histopathology; Human; In Vitro; Infection; Inhalation; Length; Lipid III; Lipids; Lung; Manufacturer Name; Medical; Methods; Modeling; Monkeys; Mycobacterium tuberculosis; Onset of illness; Organ; Oryctolagus cuniculus; Pathogenicity; Peptidoglycan; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Plasma; Plasma Proteins; Pneumococcal Infections; Preparation; Production; Program Development; Property; Proteins; Resistance; Resistance development; Running; Safety; Sampling; Septicemia; Serum; Skin; Source; Staphylococcus aureus; Structure; Teichoic Acids; Testing; Texas; Therapeutic; Tissues; Toxicology; Universities; Work; animal efficacy; animal rule; biothreat; combat; drug resistant pathogen; efficacy study; methicillin resistant Staphylococcus aureus; microbial; minimal inhibitory concentration; mutant; nonhuman primate; pathogen; preclinical development; resistance frequency; scale up; side effect; therapy development; therapy resistant; weapons

ABSTRACT The goal of this project is to continue developing teixobactin (TXB) as an antibiotic to combat weaponized anthrax. This work will be done in parallel to an ongoing preclinical development program, which is advancing TXB for treating infections caused by other serious pathogens such as methicillin resistant Staphylococcus aureus (MRSA). TXB has shown excellent efficacy in several animal models of infection, including a rabbit model of inhalation anthrax recently run at the University of Texas Medical Branch (Galveston, TX). Due to TXB’s unusual mechanism of action – binding two different bacterial cell wall targets, neither of which is a protein – TXB represents an example of a compound that is exceptionally free of resistance development and thus is an excellent candidate as a countermeasure for anthrax. The work in this grant will include the following Specific Aims: Aim 1 will provide at least 50 grams of non-cGMP teixobactin to fulfill all studies in the proposal. In addition, at least 200 grams of cGMP material will be produced at a contract manufacturer for planned future studies. Aim 2 will focus on the following studies to further understand TXB’s in vitro properties: (a) MIC testing against a panel of key B. anthracis isolates, including isolates resistant to current anthrax drugs; (b) determine B. anthracis resistance frequency to teixobactin; and (c) protein binding studies using rabbit, nonhuman primate (NHP), and human serum to determine free drug levels. Aim 3 will determine the minimal therapeutic TXB dose in the rabbit anthrax efficacy model, with associated pharmacokinetic (PK) profiling and histopathology. The information in Aim 3, in addition to the toxicology, safety and PK/PD studies being run in parallel with this project, will help inform NHP and human dosing. At the conclusion of this grant, TXB will be prepared to enter a GLP-compliant, NHP inhalation anthrax study and a Phase I clinical study, all in support of FDA approval for treating anthrax under the Animal Rule.

抽象的 该项目的目的是继续开发远程脱发（TXB）作为一种抗生素 战斗武器化的炭疽病。这项工作将与正在进行的临床前平行完成 开发计划，正在推进TXB用于治疗其他严重性引起的感染 病原体，例如金黄色葡萄球菌（MRSA）。 TXB已显示 在几种感染动物模型中，包括感染的兔子模型的效率出色 炭疽最近在德克萨斯大学医学分公司（德克萨斯州加尔维斯顿）竞选。由于TXB 不寻常的作用机理 - 结合两个不同的细菌细胞壁目标，这两个靶标都不是 蛋白质 - TXB代表了异常无电阻的化合物的一个例子 因此，发展是炭疽病的对策的出色候选人。 这笔赠款中的工作将包括以下特定目标：AIM 1至少提供 50克非CGMP电脱角蛋白旨在完成该提案中的所有研究。另外，至少200个 CGMP材料的克将在合同制造商的计划未来研究中生产。 AIM 2将集中于以下研究，以进一步了解TXB的体外特性：（a）MIC 针对一系列钥匙。炭分离株进行测试，包括抗电流炭疽的分离株 毒品； （b）确定触红细胞触及触及远非分裂症的抗性频率； （c）蛋白质结合 使用兔子，非人类灵长类动物（NHP）和人血清来确定自由药物水平的研究。 AIM 3将确定兔炭疽效果模型中最小的热TXB剂量，并以 相关的药代动力学（PK）分析和组织病理学。 AIM 3中的信息 除毒理学，安全性和PK/PD研究与该项目并行运行，将有助于 通知NHP和人类给药。 在这笔赠款的结论结束时，TXB将准备进入符合GLP的NHP 吸入炭疽研究和I期临床研究，所有这些都支持FDA批准用于治疗 动物规则下的炭疽病。