Teixobactin Development for Anthrax

摘要 该项目的目标是继续开发替克生(TXB)作为抗生素来治疗 战斗武器化炭疽病。这项工作将与正在进行的临床前工作并行进行 发展计划，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已经显示出 在几种动物感染模型中表现出色，包括兔吸入感染模型 最近在德克萨斯大学医学分校(德克萨斯州加尔维斯顿)运行的炭疽病。由于血栓素B 结合两个不同细菌细胞壁靶标的不寻常的作用机制，这两个靶标都不是 蛋白质-血栓素B代表了一种特殊无抗性的化合物。 因此，作为炭疽病的对策，它是一个极好的候选者。 这笔赠款中的工作将包括以下具体目标：AIM 1将至少提供 50克非cGMP teixobactin以完成提案中的所有研究。此外，至少有200名 一家合同制造商将生产一克cGMP材料，用于计划中的未来研究。 AIM 2将侧重于以下研究，以进一步了解TXB的体外特性：(A)最低抑菌浓度 对一组关键的炭疽杆菌分离物进行测试，包括对当前炭疽菌耐药的分离物 药物；(B)确定炭疽杆菌对teixobactin的抗药性频率；和(C)蛋白质结合 使用兔、非人灵长类动物(NHP)和人血清来确定游离药物水平的研究。 目的3将在兔炭疽病疗效模型中确定最小治疗性TXB剂量， 联合药代动力学(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研究外，与该项目并行进行的研究也将有所帮助 通知NHP和人工配药。 在这笔赠款结束时，TXB将准备进入符合GLP的NHP 吸入性炭疽病研究和I期临床研究，均支持FDA批准用于治疗 动物法则下的炭疽热。

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.