Developing Teixobactin for Respiratory Infections

开发用于呼吸道感染的 Teixobactin

• 批准号: 10201364
• 负责人: Dallas Hughes
• 金额: $ 146.95万
• 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/10201364
• 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 Airway 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调查我们新发现的远程角膜激活的潜力 抗生素，治疗呼吸道感染。正如CDC在2019年报告的那样，由耐药性引起的肺炎 肺炎链球菌以及耐甲氧西林金黄色葡萄球菌（MRSA）被认为 严重威胁。此外，与19的呼吸细菌共感染最近已被认为是 重大问题。嗜血杆菌影响力和卡他氏菌是另外两种呼吸道病原体 在患有慢性阻塞性肺部疾病的患者中特别有问题，是 社区获得的细菌性肺炎（CABP）。 电视分泌蛋白的最显着，最出乎意料的特性是缺乏任何可检测到的抵抗力 这个化合物。 Teixobactin达到了两个相关的目标：Lipid II，PepperyDoglycan和脂质III的前体，前体的前体 壁te曲酸。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。自从我们发现电远非分激素以来，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芽孢杆菌在内的任何物种。 Teixobactin高度高 在大腿，肺和血液感染的动物模型中容易。动物感染模型预测人类 急性皮肤和皮肤结构感染（ABSSI）的电远光果蛋白剂量将非常低（≤1mg/kg/day），其中 有利，因为低剂量可以最大程度地减少副作用并降低制造成本。 Teixobactin在临床前发育中是一种静脉注射（IV）药物，用于治疗皮肤感染引起的 由MRSA等病原体。 12月举行了与FDA举行的投票前新药（IND）会议 2018年FDA通常同意我们的发展计划。计划了ABSSI的IND提交 2022年。 在该项目中，AIM 1将为所有拟议的研究产生足够的远程远程分泌蛋白。 AIM 2将进行 AIM 3将测试体外敏感性，杆菌 在呼吸道感染最近的临床分离株中，活性，抗生素后作用（PAE）和耐药性。目标4 将准备并提交IND申请以静脉治疗呼吸道感染。 AIM 5将探索 TXB给药的替代途径（吸入和肌内输送），这尤其是 可用于门诊治疗呼吸道和其他感染。这些项目成功完成， 我们将证明远远黑乳素对治疗药物抗药性呼吸道感染和 探索了更方便的TXB管理路线。