Developing Teixobactin for Respiratory Infections

摘要：这项提案的主要目的是研究我们新发现的替克生的潜力。 抗生素，用于治疗呼吸道感染。据疾病预防控制中心2019年报告，耐药引起的肺炎 肺炎链球菌和耐甲氧西林金黄色葡萄球菌(MRSA)也被考虑。 严重的威胁。此外，呼吸道细菌与新冠肺炎的联合感染最近被认为是一种 这是个大问题。流感嗜血杆菌和卡他摩拉氏菌是另外两种呼吸道病原体 在慢性阻塞性肺疾病患者中尤其有问题，是导致 社区获得性细菌性肺炎(CABP) Teixobactin最显著和最意想不到的特性是对 就是这个院子。Teixobactin作用于两个相关的靶点--脂蛋白II，肽聚糖前体和脂蛋白III，肽聚糖前体 沃氏磷壁酸。这些高度保守的靶标不是可变的--它们不是蛋白质，也不是直接的 由DNA编码。自从我们发现teixobactin以来，我们和其他人未能在 包括金黄色葡萄球菌、结核分枝杆菌或炭疽杆菌在内的任何物种。替科巴坦具有很高的 对大腿、肺部和血液感染的动物模型有效。动物感染模型预测，人类 治疗急性皮肤和皮肤结构感染的替考巴汀剂量将非常低(≤1毫克/公斤/天)， 是有利的，因为低剂量可以最大限度地减少副作用并降低制造成本。 替科巴坦是一种静脉(IV)药物，用于治疗皮肤感染，处于临床前开发阶段 被MRSA等病原体感染。与FDA的新药研究前会议于12月举行 2018年，FDA大体上同意我们的开发计划。计划为ABSSSI提交IND 2022年。 在这个项目中，目标1将为所有拟议的研究生产足够的替克生。目标2将进行 肺炎动物模型的疗效及PK/PD研究。AIM 3将测试体外敏感性，杀菌 近期呼吸道感染临床分离株的活性、抗生素后效应(PAE)和耐药性目标4 将准备并提交静脉治疗呼吸道感染的IND申请。Aim 5将探索 TXB给药的替代途径(吸入和肌肉注射)，这将是特别 适用于呼吸道和其他感染的门诊治疗。随着这些项目的顺利完成， 我们将展示替克生在治疗耐药呼吸道感染方面的前景 探索更便捷的血栓素B给药途径。

ABSTRACT: The major goal of this proposal is to investigate the potential for teixobactin, our newly discovered antibiotic, to treat respiratory infections. As reported in 2019 by the CDC, pneumonia caused by drug resistant Streptococcus pneumoniae, as well as methicillin-resistant Staphylococcus aureus (MRSA), are considered serious threats. In addition, respiratory bacterial co-infections with Covid-19 have recently been recognized as a significant problem. Haemophilus influenzae and Moraxella catarrhalis are two other respiratory pathogens particularly problematic in patients with chronic obstructive pulmonary disease and are common causes of community-acquired bacterial pneumonia (CABP). The most remarkable, and unexpected property of teixobactin is the lack of any detectable resistance to this compound. Teixobactin hits two related targets—lipid II, precursor of peptidoglycan and lipid III, precursor of wall teichoic acid. These highly conserved targets are not mutable—they are not proteins and are not directly coded by DNA. Since our discovery of teixobactin, we and others have failed to generate resistant mutants in any species including S. aureus, Mycobacterium tuberculosis or Bacillus anthracis. Teixobactin is highly efficacious in animal models of thigh, lung and blood infections. Animal infection models predict that the human dose of teixobactin for acute skin and skin structure infections (ABSSSI) will be very low (≤1 mg/kg/day), which is advantageous, as a low dose may minimize side effects and reduce manufacturing costs. Teixobactin is in preclinical development as an intravenous (IV) drug for treating skin infections caused by pathogens such as MRSA. A pre-Investigational New Drug (IND) meeting with FDA was held in December 2018 whereby the FDA generally agreed with our development plan. An IND submission for ABSSSI is planned for 2022. In this project, Aim 1 will produce enough teixobactin for all the proposed studies. Aim 2 will conduct efficacy and PK/PD studies in animal models of pneumonia. Aim 3 will test in vitro susceptibility, bactericidal activity, post antibiotic effect (PAE) and resistance in recent clinical isolates from respiratory infections. Aim 4 will prepare and submit an IND application for intravenous treatment of a respiratory infection. Aim 5 will explore alternative routes of TXB administration (inhalation and intramuscular delivery), which would be particularly useful for outpatient treatment of respiratory and other infections. With successful completion of these projects, we will have demonstrated the promise of teixobactin for treating drug resistant respiratory infections and explored more convenient routes of TXB administration.