Teixobactin Development for Tuberculosis

摘要 这项提案的目标是研究替克生(TXB)治疗耐药结核病的潜力。 (TB)。结核病是一个主要的全球健康问题，也是第二大致死传染病。按结核病分类的不遵守规定 由于治疗时间过长，患者产生了需要更长时间治疗的耐药菌株 持续时间和不良副作用的高风险。因此，迫切需要一种更安全的药物方案， 持续时间更短，并避免抗药性。TXB最显著的特性是缺乏任何可检测到的 抵抗。这种阻力的缺乏很可能是由于其双管齐下的行动模式。血栓素B击中两个相关的 靶标-脂类II，肽聚糖前体，类脂III，壁磷壁酸前体。这些高度保守的 靶标不是可变的，因为它们不是蛋白质，也不是直接由DNA编码的。此外，一旦绑定到 它的细菌靶标TXB自我结合成大的大分子结构，从而削弱膜和 进一步促进了其强大的杀戮活动。很可能，这些结构是不可逆转的，这可以解释为什么 TXB剂量在各种动物感染模型中都是如此有效。自从发现TXB以来，我们和其他人 未能在包括结核分枝杆菌在内的任何物种中产生抗药性突变。重要的是，在最近的一次 在约翰·霍普金斯大学进行的一项研究中，TXB在经过验证的结核病兔模型中非常有效， 展示了它治疗这种毁灭性疾病的承诺。 TXB处于临床前开发阶段，是一种静脉(IV)药物，用于治疗严重的皮肤感染 被MRSA等病原体感染。在新药研究前(IND)会议上，FDA普遍同意 我们的发展计划，并计划在大约1.5至2年内提交IND。这样做的目的是 建议是继续探索TXB治疗结核病的潜力。在这个项目中，Aim 1将生产足够的TXB 所有拟议的研究。Aim 2将在小鼠的血液和肺PK研究中使用鼻腔给药 血栓素B。鼻腔给药有几个优点，包括直接将药物输送到初级 感染部位(肺部)，避免全身给药的副作用。AIM 3将使用克拉姆尼克结核病 小鼠模型，以测试单独鼻腔给药和与当前结核病药物联合使用的疗效。 Kramnik小鼠患上的肺肉芽肿更类似于人类的病变。AIM 4将使用 验证兔模型，比较静脉注射TXB单独和与其他结核病药物联合使用的疗效。 在AIMS 3和4中，TXB药物方案将与BPaL(贝达奎兰、前托马尼德、利奈唑胺)方案进行比较 目前用于耐多药结核病。随着这些研究的成功完成，我们将证明 TXB治疗耐药结核病的前景，探索了一条便捷的给药途径。

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.