Developing Teixobactin for Respiratory Infections

开发用于呼吸道感染的 Teixobactin

• 批准号: 10378726
• 负责人: Dallas Hughes
• 金额: $ 119.51万
• 依托单位: NOVOBIOTIC PHARMACEUTICALS, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-22 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10378726
• 关键词: Acute; Aerosols; Ambulatory Care; Animal Model; Animals; Antibiotics; Bacillus anthracis; Bacterial Pneumonia; COVID-19; Centers for Disease Control and Prevention (U.S.); Chemicals; Chronic Obstructive Pulmonary Disease; Clinical; Clinical Protocols; Clinical Trials; Code; Communicable Diseases; Communities; DNA; Development Plans; Dose; Drug Compounding; Drug resistance; Epithelial; Fermentation; Future; Goals; Gram-Positive Bacteria; Haemophilus influenzae; Hospitals; Human; In Vitro; Infection; Infectious Skin Diseases; Inhalation; Intramuscular; Intravenous; Investigational Drugs; Investigational New Drug Application; Lipid III; Lipids; Liquid substance; Lung infections; Macrolide-resistance; Maximum Tolerated Dose; Modeling; Moraxella catarrhalis; Morbidity - disease rate; Mus; Mycobacterium tuberculosis; Nebulizer; Pamphlets; Patients; Peptidoglycan; Pharmaceutical Preparations; Pharmacology; Pharmacology and Toxicology; Plasma; Pneumonia; Predisposition; Production; Property; Rattus; Reporting; Research; Research Personnel; Resistance; Resistance profile; Respiratory Tract Infections; Route; Safety; Sepsis; Skin; Staphylococcus aureus; Streptococcus pneumoniae; Structure; Teichoic Acids; Test Result; Testing; Therapeutic; Thigh structure; Toxicology; Ventilator; bactericide; base; co-infection; cost; improved; in vitro testing; in vivo; meetings; methicillin resistant Staphylococcus aureus; microbial; mortality; mouse model; mutant; pathogen; pharmacokinetics and pharmacodynamics; pneumonia model; preclinical development; predictive modeling; resistance frequency; respiratory; respiratory pathogen; side effect

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.

摘要：该提案的主要目标是研究我们新发现的 teixobactin 的潜力 抗生素，治疗呼吸道感染。据CDC 2019年报告，耐药性肺炎 肺炎链球菌以及耐甲氧西林金黄色葡萄球菌 (MRSA) 被认为是 严重威胁。此外，呼吸道细菌与 Covid-19 的合并感染最近被认为是一种 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 对于患有慢性阻塞性肺病的患者来说尤其成问题，并且是慢性阻塞性肺疾病的常见原因 社区获得性细菌性肺炎（CABP）。 teixobactin 最显着且意想不到的特性是缺乏任何可检测到的耐药性 这种化合物。 Teixobactin 击中两个相关靶标：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是不可变的——它们不是蛋白质，也不直接 由DNA编码。自从我们发现 teixobactin 以来，我们和其他人未能在 任何物种，包括金黄色葡萄球菌、结核分枝杆菌或炭疽杆菌。泰克巴汀具有高度 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 泰克巴汀治疗急性皮肤和皮肤结构感染（ABSSSI）的剂量将非常低（≤1 mg/kg/天），这 是有利的，因为低剂量可以最小化副作用并降低制造成本。 Teixobactin 正处于临床前开发阶段，作为一种静脉注射 (IV) 药物，用于治疗引起的皮肤感染 由 MRSA 等病原体引起。 12 月与 FDA 举行了新药研究前 (IND) 会议 2018 年 FDA 总体同意我们的开发计划。计划向 ABSSSI 提交 IND 申请 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巴汀。目标2将进行 肺炎动物模型中的疗效和 PK/PD 研究。目标3将测试体外药敏性、杀菌性 最近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 将准备并提交呼吸道感染静脉治疗的 IND 申请。目标5将探索 TXB 给药的替代途径（吸入和肌肉注射），这将特别重要 可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 在治疗耐药性呼吸道感染方面的前景， 探索更便捷的TXB给药途径。