Teixobactin Development for Anthrax

摘要 该项目的目标是继续开发teixobactin（TXB）作为抗生素， 对抗炭疽武器这项工作将与正在进行的临床前研究平行进行。 开发计划，该计划正在推进TXB用于治疗由其他严重疾病引起的感染。 病原体如耐甲氧西林金黄色葡萄球菌（MRSA）。TXB显示 在几种动物感染模型中具有优异的功效，包括吸入的兔模型 炭疽最近在德克萨斯大学医学分支（加尔维斯顿，德克萨斯州）运行。由于TXB的 不寻常的作用机制-结合两种不同的细菌细胞壁靶点，两者都不是 TXB蛋白代表了一种化合物的例子， 发展，因此是作为炭疽对策的优秀候选者。 这项资助的工作将包括以下具体目标：目标1将提供至少 50 g非cGMP teixobactin，以完成提案中的所有研究。此外，至少200名 将在合同生产商处生产10克cGMP材料，用于计划的未来研究。 目的2将着重于以下研究以进一步了解TXB的体外性质：（a）MIC 对照钥匙B的面板进行测试。炭疽分离株，包括对现有炭疽有抗性的分离株 药物;（B）测定B。炭疽菌对teixobactin的抗性频率;和（c）蛋白结合 使用兔、非人灵长类动物（NHP）和人血清测定游离药物水平的研究。 目的3将确定兔炭疽疗效模型中的最小治疗TXB剂量， 相关的药代动力学（PK）分析和组织病理学。目标3中的信息， 除了毒理学，安全性和PK/PD研究正在与本项目并行运行，将有助于 告知NHP和人类剂量。 在这项赠款结束时，TXB将准备进入一个符合GLP的NHP 吸入性炭疽研究和I期临床研究，所有这些都支持FDA批准治疗 炭疽病在动物规则下

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.