Teixobactin Development for Tuberculosis

Teixobactin 治疗结核病的开发

• 批准号: 10546221
• 负责人: Dallas Hughes
• 金额: $ 100万
• 依托单位: NOVOBIOTIC PHARMACEUTICALS, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10546221
• 关键词: Acute; Animal Model; Animals; Anthrax disease; Antibiotics; Antitubercular Antibiotics; Bacteremia; Binding; Blood; C3HeB/FeJ Mouse; COVID-19; Cause of Death; Cell Wall; Cell membrane; Chronic; Code; Collaborations; DNA; Development; Development Plans; Disease; Dose; Drug Combinations; Drug Exposure; Drug Kinetics; Drug resistance; Drug resistance in tuberculosis; Epithelial; Exhibits; Fermentation; Goals; Gram-Positive Bacteria; HIV/TB; Human; In Vitro; Infection; Infectious Agent; Infectious Skin Diseases; Inhalation Therapy; Intranasal Administration; Intravenous; Investigational Drugs; Lesion; Linezolid; Lipid III; Lipids; Liquid substance; Lung; Membrane; Modeling; Molecular Structure; Multi-Drug Resistance; Multidrug-Resistant Tuberculosis; Mus; Mycobacterium tuberculosis; Necrosis; Oral; Oral Tuberculosis; Oryctolagus cuniculus; Patient Noncompliance; Patients; Peptidoglycan; Persons; Pharmaceutical Preparations; Phase; Plasma; Pneumonia; Primary Infection; Production; Property; Pulmonary Pathology; Pulmonary Tuberculosis; Pyrazinamide; Regimen; Relapse; Resistance; Resistance development; Route; Site; Skin; Streptococcus pneumoniae; Structure; Teichoic Acids; Testing; Time; Toxic effect; Tuberculosis; Universities; X-Ray Computed Tomography; arm; bactericide; cell killing; comparative efficacy; efficacy study; efficacy testing; extensive drug resistance; global health; high risk; isoniazid; lung lesion; meetings; methicillin resistant Staphylococcus aureus; microbial; mouse model; multiple drug use; mutant; non-compliance; non-invasive monitor; novel antibiotic class; pathogen; pneumonia model; preclinical development; pulmonary granuloma; resistant strain; side effect; synergism; treatment duration; tuberculosis drugs

ABSTRACT The goal of this proposal is to investigate the potential for teixobactin (TXB) to treat drug-resistant tuberculosis (TB). TB is a major global health issue and second largest killer by an infectious agent. Non-compliance by TB patients due to lengthy treatment times have resulted in drug-resistant strains that require longer treatment durations and a high risk of adverse side effects. Thus, there is a pressing need for a drug regimen that is safer, shorter in duration and avoids drug resistance. The most remarkable property of TXB is the lack of any detectable resistance. This lack of resistance is most likely due to its two-pronged mode of action. TXB hits two related targets—lipid II, precursor of peptidoglycan and lipid III, precursor of wall teichoic acid. These highly conserved targets are not mutable, as they are not proteins and are not directly coded by DNA. In addition, once bound to its bacterial target, TXB self-associates into large macromolecular structures that weaken the membrane and further contribute to its potent killing activity. Likely, these structures are irreversible, which can explain how low TXB doses are so effective in various animal models of infection. Since discovering TXB, we and others have failed to generate resistant mutants in any species including Mycobacterium tuberculosis. Importantly, in a recent study conducted at John Hopkins University, TXB was highly efficacious in a validated rabbit model of TB, demonstrating its promise to treat this devastating disease. TXB is in preclinical development as an intravenous (IV) drug for treating serious skin infections caused by pathogens such as MRSA. At a pre-Investigational New Drug (IND) meeting, the FDA generally agreed with our development plan, and an IND submission is planned in approximately 1.5 to 2 years. The goal of this proposal is to continue exploring TXB’s potential to treat TB. In this project, Aim 1 will produce enough TXB for all the proposed studies. Aim 2 will conduct blood and lung PK studies in mice using intranasal administration of TXB. Intranasal administration offers several advantages, including delivering the drug directly to the primary site of infection (lung) and avoiding side effects with drugs delivered systemically. Aim 3 will use the Kramnik TB mouse model to test the efficacy of intranasal TXB delivered alone and in combination with current TB drugs. Kramnik mice develop pulmonary granulomas that more closely resembled human lesions. Aim 4 will use a validated rabbit model to compare the efficacy of IV-delivered TXB alone and in combination with other TB drugs. In Aims 3 and 4, TXB drug regimens will be compared to the BPaL (bedaquiline, pretomanid, linezolid) regimen currently used for multidrug resistant TB. With successful completion of these studies, we will have demonstrated the promise of TXB for treating drug-resistant TB and explored a convenient route of administration.

抽象的 该提案的目的是调查远程脱发（TXB）治疗耐药性结核病的潜力 （TB）。结核病是全球主要的健康问题，也是传染毒剂的第二大杀手。结核病不合规 由于长期治疗时间导致的患者导致耐药菌株需要更长的治疗 持续时间和不良副作用的高风险。那是对安全的药物方案的迫切需求， 持续时间短，避免耐药性。 TXB最显着的特性是缺乏任何可检测到的 反抗。这种缺乏抵抗力很可能是由于其两管齐的作用方式。 TXB命中了两个相关的 靶标-Plipid II，PepperyDoglycan和脂质III的前体，壁teichoic酸的前体。这些高度保守 靶标不是可变的，因为它们不是蛋白质，也不是由DNA直接编码的。另外，一旦束缚 其细菌靶标，TXB自我缔合成大的大分子结构，从而削弱了膜和 进一步有助于其潜在的杀戮活动。这些结构可能是不可逆转的，可以解释 TXB剂量在各种感染动物模型中非常有效。自从发现TXB以来，我们和其他人都有 未能在包括结核分枝杆菌在内的任何物种中产生抗性突变体。重要的是，在最近的一个 TXB在约翰·霍普金斯大学（John Hopkins University）进行的研究中，在经过验证的TB兔模型中效率很高。 证明其有望治疗这种毁灭性疾病。 TXB正在临床前发育中作为一种静脉（IV）药物，用于治疗严重的皮肤感染 由MRSA等病原体。在投票前的新药（IND）会议上，FDA普遍同意 我们的开发计划和IND提交计划在大约1.5到2年内计划。目标的目标 提案是继续探索TXB治疗结核病的潜力。在这个项目中，AIM 1将产生足够的TXB 所有提出的研究。 AIM 2将使用鼻内给药的小鼠进行血液和肺PK研究 TXB。鼻内管理提供了几个优势，包括将药物直接输送到主要 感染部位（肺）并避免系统地递送药物的副作用。 AIM 3将使用Kramnik TB 小鼠模型测试单独递送并与当前结核病药物结合使用的鼻内TXB效率。 kramnik小鼠会形成肺肉芽肿，更像人类病变。 AIM 4将使用 经过验证的兔模型，以比较单独使用IV授予的TXB并与其他结核病药物的效率进行比较。 在AIMS 3和4中，将将TXB药物方案与BPAL（bedaquiline，pipomanid，linezolid）方案进行比较 目前用于多药耐药结核病。通过成功完成这些研究，我们将证明 TXB对治疗耐药结核病的承诺并探索了方便的管理途径。