Teixobactin Development for Anthrax

摘要 该项目的目标是继续开发 teixobactin (TXB) 作为抗生素 对抗武器化的炭疽病。这项工作将与正在进行的临床前试验同时进行 开发计划，该计划正在推进 TXB 治疗其他严重感染引起的感染 病原体，例如耐甲氧西林金黄色葡萄球菌 (MRSA)。 TXB已显示 在多种动物感染模型（包括兔子吸入模型）中具有出色的疗效 炭疽病最近在德克萨斯大学医学分部（德克萨斯州加尔维斯顿）进行。由于 TXB 不寻常的作用机制——结合两个不同的细菌细胞壁目标，这两个目标都不是 蛋白质 – TXB 代表了一种特别没有耐药性的化合物的例子 发展，因此是炭疽病对策的优秀候选者。 这笔赠款的工作将包括以下具体目标： 目标 1 将至少提供 50 克非 cGMP teixobactin 来完成提案中的所有研究。此外，至少有200 克 cGMP 材料将由合同制造商生产，用于计划的未来研究。 目标 2 将重点开展以下研究，以进一步了解 TXB 的体外特性： (a) MIC 针对一组关键炭疽芽孢杆菌分离株进行测试，包括对当前炭疽杆菌具有抗性的分离株 毒品； (b)确定炭疽芽孢杆菌对替克巴汀的耐药频率； (c) 蛋白质结合 使用兔子、非人灵长类动物 (NHP) 和人血清来测定游离药物水平的研究。 目标 3 将确定兔炭疽疗效模型中的最小治疗 TXB 剂量，其中 相关的药代动力学（PK）分析和组织病理学。目标 3 中的信息 除了与该项目同时进行的毒理学、安全性和 PK/PD 研究之外，还将有助于 告知 NHP 和人体剂量。 在本次拨款结束时，TXB 将准备进入符合 GLP 标准的 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 动物规则下的炭疽病。

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.