Novel mycobacterial translocase I inhibitors - a new class of anti-TB drugs

新型分枝杆菌易位酶 I 抑制剂——一类新型抗结核药物

• 批准号: 7612382
• 负责人: VENKATA M REDDY
• 金额: $ 79.39万
• 依托单位: SEQUELLA, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7612382
• 关键词: Antibiotics; Antitubercular Agents; Bacteria; Biological Availability; Caring; Cells; Chemicals; Chronic; Class; Clinical Research; Condition; Cytolysis; Daily; Development; Diagnosis; Disease; Disease model; Dose; Drug Delivery Systems; Drug Efflux; Drug Formulations; Drug Kinetics; Drug resistance; Drug resistance in tuberculosis; Ethambutol; Exposure to; Genus Mycobacterium; Grant; Half-Life; In Vitro; Investigational Drugs; Liposomes; Liquid substance; Lung; Mammals; Methods; Micelles; Modification; Multi-Drug Resistance; Mus; Mycobacterium tuberculosis; Numbers; Oral; P-Glycoprotein; P-Glycoproteins; Particulate; Patients; Phagocytosis; Phagosomes; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Physicians; Physiological; Property; Reporting; Solubility; Standards of Weights and Measures; Streptomycin; System; Testing; Thinking; Time; Tissues; Today; Toxicology; Treatment Protocols; Tuberculosis; Vitamin E; alpha-tocopheryl polyethylene glycol succinate; analog; antimicrobial; bactericide; base; chemotherapy; cost; day; drug development; drug resistant bacteria; drug standard; efflux pump; improved; in vivo; inhibitor/antagonist; isoniazid; killings; macrophage; mouse model; mutant; mycobacterial; nanoparticle; novel; particle; preclinical study; prevent; size; translocase; tuberculosis drugs; tuberculosis treatment

DESCRIPTION (provided by applicant): Physicians treating tuberculosis (TB) today are in desperate need of new, efficient, and effective antibiotics to improve both time of treatment and durability of cure in multi-drug resistant (MDR) as well as uncomplicated TB. In the completed Phase 1 grant (Final Report below), we evaluated an exciting new drug candidate, SQ641. SQ641 has activity superior to Isoniazid (INH) and all other TB drugs and, under appropriate conditions, rapidly reduces Mycobacteria in our two best TB disease models; macrophages and mice. We briefly describe the drug properties, including its exceptional bactericidal activity, its target and mechanism of action (Translocase I), and our efforts to date to develop an oral formulation. In this Phase 2 proposal, we outline the next steps to identify a commercially viable oral formulation(s) of SQ641 for oral treatment regimens, and a parenteral formulation(s) which would have the potential to create a new treatment paradigm; a single, parenteral dose administered at the time of diagnosis. Compared to the current standard of care for TB, both formulations, and associated treatment regimens would dramatically and quickly reduce bacteria in tissues and drastically shorten and improve TB treatment time. INH is used for the first 2 mo of intensive chemotherapy as a cornerstone drug of TB therapy because of its ability to quickly kill rapidly replicating Mycobacterium tuberculosis (MTB) in infected tissues and reduce the number of infectious bacteria in pulmonary secretions. As evidenced by Early Bactericidal Activity (EBA) clinical studies, INH is clearly the most potent of all currently available TB drugs. Interestingly, compared to SQ641, INH is a relatively slow-acting drug in vitro that requires several days to kill MTB, and has a post antibiotic effect (PAE) of only 17 hr. Based on a relatively short half- life, the drug is administered daily. Despite daily administration, recent studies demonstrate that the number of viable bacteria remains sufficient to promote physiologic (Siddiqi et al. 2007) and genotypic drug-resistant bacteria. After 48 hr of exposure to INH, ~10% of MTB are killed, but still morphologically intact. In contrast, SQ641 kills 90% of MTB in this timeframe and the bacteria are lysed (liquid cultures are clear). Moreover, SQ641 has a PAE of 55 hr, 3 times the INH PAE. The best way to prevent drug resistance is to act quickly, before bacteria have a chance to adjust to the presence of the drug. SQ641 is highly effective in preventing development of drug resistant mutants in vitro and has marked synergistic activity in vitro with several antituberculars: Ethambutol (EMB), streptomycin, and the new Sequella drug, SQ109. SQ641 has excellent in vitro activity against drug susceptible and MDR MTB, M. kansasii, M. abscessus, and M. avium, and could also be developed for nontuberculous mycobacterial (NTM) diseases. In spite of the remarkable antibiotic properties of SQ641 against Mycobacteria, a practical method to deliver this drug remains a challenge. We discovered that SQ641 activates the P-glycoprotein (P-gp) drug efflux pump in macrophages, and therefore does not accumulate to bactericidal concentrations inside these important cells that harbor MTB in infected mammals. As expected, P-gp efflux inhibitors markedly enhanced the activity of SQ641 against intracellular MTB; SQ641 was equivalent to or better than INH (the most potent single drug in this test system). In mice, orally administered SQ641 is poorly absorbed. For numerous reasons (patient acceptability, convenience, and cost), oral delivery is the preferred method to administer TB therapy. Poor bioavailability combined with rapid efflux from macrophages meant thinking creatively about drug delivery. Fortunately, we solved both efflux and insolubility problems by combining SQ641 with TPGS, a vitamin E analogue routinely used to improve drug solubility and hence bioavailability (EASTMAN and Company 2005). Stable, 4-6?m (~ the size of Mycobacteria) SQ641-containing TPGS particles were constructed. These particles were easily phagocytosed by macrophages and SQ641 was released inside phagosomes to efficiently and effectively kill intracellular MTB. In both macrophages and mouse models of TB, SQ641/TPGS formulation was as effective as INH. In this Phase 2 proposal, we will evaluate various methods (chemical modification to enhance solubility, alter drug-P-gp interactions, and develop appropriate commercial delivery systems) to solubilize SQ641 and optimize its delivery in vivo. We will explore formulations to determine whether this potent antimicrobial can be delivered orally (combined with current standard-of-care TB drugs or as a replacement for one or more of these drugs) and/or should be delivered parenterally to initiate TB chemotherapy and provide early and prolonged bacterial clearance during the intensive phase of TB treatment.

描述（由申请人提供）：当今治疗结核病（TB）的医生迫切需要新型、高效且有效的抗生素，以缩短耐多药（MDR）和无并发症结核病的治疗时间和治愈持久性。在已完成的第一阶段资助（下面的最终报告）中，我们评估了一种令人兴奋的新候选药物 SQ641。 SQ641 的活性优于异烟肼 (INH) 和所有其他结核病药物，并且在适当的条件下，可迅速减少我们两个最佳结核病模型中的分枝杆菌；巨噬细胞和小鼠。我们简要描述了该药物的特性，包括其卓越的杀菌活性、其靶点和作用机制（Translocase I），以及我们迄今为止开发口服制剂的努力。在此第 2 阶段提案中，我们概述了后续步骤，以确定用于口服治疗方案的商业上可行的 SQ641 口服制剂，以及有可能创造新治疗范例的肠胃外制剂；诊断时给予单次肠胃外剂量。与目前的结核病护理标准相比，这两种制剂和相关治疗方案将显着且快速地减少组织中的细菌，并大大缩短和改善结核病治疗时间。 INH 作为结核病治疗的基础药物用于前 2 个月的强化化疗，因为它能够快速杀死感染组织中快速复制的结核分枝杆菌 (MTB)，并减少肺部分泌物中感染性细菌的数量。早期杀菌活性 (EBA) 临床研究证明，INH 显然是目前所有可用结核病药物中最有效的。有趣的是，与SQ641相比，INH是一种体外作用相对缓慢的药物，需要数天才能杀死MTB，并且抗生素后效应（PAE）仅为17小时。由于半衰期相对较短，该药物每天给药。尽管每天给药，最近的研究表明，活细菌的数量仍然足以促进生理（Siddiqi 等人，2007）和基因型耐药细菌。接触 INH 48 小时后，约 10% 的 MTB 被杀死，但形态仍然完好。相比之下，SQ641 在此时间范围内杀死 90% 的 MTB，并且细菌被裂解（液体培养物是透明的）。此外，SQ641的PAE为55小时，是INH PAE的3倍。防止耐药性的最佳方法是在细菌有机会适应药物存在之前迅速采取行动。 SQ641 在体外能够高度有效地预防耐药突变体的形成，并且在体外与几种抗结核药物具有显着的协同活性：乙胺丁醇 (EMB)、链霉素和新的 Sequella 药物 SQ109。 SQ641 对药物敏感和耐多药 MTB、堪萨斯分枝杆菌、脓肿分枝杆菌和鸟分枝杆菌具有优异的体外活性，也可用于非结核分枝杆菌 (NTM) 疾病。尽管 SQ641 对分枝杆菌具有显着的抗生素特性，但递送这种药物的实用方法仍然是一个挑战。我们发现，SQ641 激活巨噬细胞中的 P-糖蛋白 (P-gp) 药物外排泵，因此不会在受感染哺乳动物中携带 MTB 的这些重要细胞内积累至杀菌浓度。正如预期的那样，P-gp 外排抑制剂显着增强了 SQ641 对抗细胞内 MTB 的活性； SQ641相当于或优于INH（该测试系统中最有效的单一药物）。在小鼠中，口服 SQ641 吸收不良。出于多种原因（患者可接受性、便利性和成本），口服给药是结核病治疗的首选方法。生物利用度差加上巨噬细胞快速流出意味着需要创造性地思考药物输送。幸运的是，我们通过将 SQ641 与 TPGS 结合解决了外排和不溶性问题，TPGS 是一种维生素 E 类似物，通常用于提高药物溶解度，从而提高生物利用度（EASTMAN and Company 2005）。构建了包含 TPGS 的稳定的 4-6μm（~分枝杆菌大小）SQ641 颗粒。这些颗粒很容易被巨噬细胞吞噬，SQ641被释放到吞噬体内，高效、有效地杀死细胞内的MTB。在结核病的巨噬细胞和小鼠模型中，SQ641/TPGS 制剂与 INH 一样有效。在此第 2 阶段提案中，我们将评估各种方法（化学修饰以提高溶解度、改变药物-P-gp 相互作用以及开发适当的商业递送系统）来溶解 SQ641 并优化其体内递送。我们将探索配方，以确定这种有效的抗菌药物是否可以口服给药（与当前的标准治疗结核病药物相结合，或作为其中一种或多种药物的替代品）和/或应该肠胃外给药以启动结核病化疗，并在结核病强化治疗阶段提供早期和长期的细菌清除。