Teixobactin Development for Tuberculosis

摘要 该提案的目的是研究替沙菌素（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，也是第二大传染性杀手。按结核病分列的不遵守情况 由于治疗时间过长，导致患者产生耐药菌株，需要更长时间的治疗 持续时间和高风险的不良副作用。因此，迫切需要一种更安全的药物方案， 持续时间短，避免耐药性。TXB最显著的特性是缺乏任何可检测的 阻力这种缺乏抵抗力很可能是由于其双管齐下的行动模式。TXB击中两个相关的 目标-脂质II，肽聚糖的前体和脂质III，壁磷壁酸的前体。这些高度保守 靶点不是可变的，因为它们不是蛋白质，也不是由DNA直接编码的。此外，一旦绑定到 它的细菌靶点TXB自身结合成大的大分子结构，削弱膜， 进一步有助于其有效的杀伤活性。很可能，这些结构是不可逆的，这可以解释为什么 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 未能在包括结核分枝杆菌在内的任何物种中产生耐药突变体。重要的是，在最近的 在约翰霍普金斯大学进行的一项研究中，TXB在经验证的TB兔模型中非常有效， 展示了它治疗这种毁灭性疾病的前景。 TXB是临床前开发的静脉注射（IV）药物，用于治疗严重的皮肤感染引起的 例如MRSA。在一次新药临床试验（IND）前会议上，FDA普遍同意 我们的开发计划，并计划在大约1.5至2年内提交IND。这个目标 该提案是继续探索TXB治疗结核病的潜力。在这个项目中，目标1将产生足够的TXB， 所有建议的研究。目的2将使用鼻内给药在小鼠中进行血液和肺PK研究 TXB。鼻内给药提供了几个优点，包括将药物直接递送到原发灶。 感染部位（肺部），并避免全身给药的副作用。Aim 3将使用Kramnik TB 小鼠模型，以测试单独递送的鼻内TXB和与当前TB药物组合递送的鼻内TXB的功效。 Kramnik小鼠出现了与人类病变更相似的肺肉芽肿。Aim 4将使用 经验证的兔模型，以比较IV递送的TXB单独和与其他TB药物组合的功效。 在目标3和4中，将比较TXB药物方案与BPaL（贝达喹啉、pretomanid、利奈唑胺）方案 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， 探讨了TXB治疗耐药结核病的前景，并探索了一种方便的给药途径。

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.