Developing Teixobactin for Respiratory Infections

摘要：本研究的主要目的是研究我们新发现的teixobactin的潜力。 抗生素，治疗呼吸道感染。根据CDC在2019年的报告，耐药引起的肺炎 肺炎链球菌以及耐甲氧西林金黄色葡萄球菌（MRSA）被认为是 严重的威胁。此外，呼吸道细菌合并感染与Covid-19最近被认为是 重大问题。流感嗜血杆菌和卡他莫拉菌是另外两种呼吸道病原体 在慢性阻塞性肺病患者中尤其成问题，并且是 社区获得性细菌性肺炎（CABP） teixobactin最显著和出乎意料的特性是缺乏任何可检测到的对 这个化合物。Teixobactin击中两个相关的靶标-脂质II，肽聚糖的前体和脂质III，肽聚糖的前体。 壁磷壁酸这些高度保守的靶标不是可变的--它们不是蛋白质，也不直接 由DNA编码。自从我们发现teixobactin以来，我们和其他人都未能产生耐药突变体。 包括S.金黄色葡萄球菌、结核分枝杆菌或炭疽杆菌。Teixobactin是一种高度 在大腿、肺和血液感染的动物模型中有效。动物感染模型预测， 用于急性皮肤和皮肤结构感染（ABSSSI）的替沙菌素剂量将非常低（≤1 mg/kg/天）， 是有利的，因为低剂量可以使副作用最小化并降低制造成本。 Teixobactin是一种静脉注射（IV）药物，用于治疗皮肤感染， 例如MRSA。12月与FDA举行了一次新药研究前会议 2018年，FDA基本同意我们的开发计划。计划提交ABSSSI的IND申请 到2022年 在这个项目中，目标1将产生足够的teixobactin用于所有拟议的研究。目标2将进行 在肺炎动物模型中的功效和PK/PD研究。目的3将测试体外敏感性，杀菌 活性，抗生素后效应（PAE）和耐药性在最近的临床分离的呼吸道感染。目标4 将准备并提交呼吸道感染静脉治疗的IND申请。Aim 5将探索 TXB给药的替代途径（吸入和肌内递送），这将特别 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， 我们将证明teixobactin治疗耐药呼吸道感染的前景， 探索更方便的TXB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.