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: 7677957
• 负责人: VENKATA M REDDY
• 金额: $ 79.57万
• 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/7677957
• 关键词: Antibiotics; Antitubercular Agents; Bacteria; Biological Availability; Caring; Cells; Chemicals; Chronic; Clinic; Clinical Research; Cytolysis; Data; 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; Hour; In Vitro; Investigational Drugs; Liposomes; Liquid substance; Lung; Mammals; Methods; Micelles; Modification; Multi-Drug Resistance; Mus; Mycobacterium tuberculosis; Oral; P-Glycoprotein; P-Glycoproteins; Particulate; Patients; Phagocytosis; Phagosomes; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Physicians; Physiological; Property; Reporting; Resistance; Solubility; Streptomycin; System; Testing; Thinking; Time; Tissues; Toxicology; Treatment Protocols; Tuberculosis; Vitamin E; alpha-tocopheryl polyethylene glycol succinate; analog; antimicrobial; bactericide; base; chemotherapy; cost; drug candidate; drug development; drug resistant bacteria; drug standard; efflux pump; improved; in vitro activity; in vivo; inhibitor/antagonist; isoniazid; killings; macrophage; mouse model; mutant; mycobacterial; nanoparticle; novel; particle; preclinical study; prevent; standard of care; 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(申请人提供)：当今治疗结核病(TB)的医生迫切需要新的、高效和有效的抗生素，以提高多药耐药(MDR)和简单结核病的治疗时间和治愈持久性。在完成的第一阶段拨款(最终报告如下)中，我们评估了一种令人兴奋的新药候选药物SQ641。SQ641的活性优于异烟肼(INH)和所有其他结核病药物，并在适当的条件下，在我们最好的两种结核病模型--巨噬细胞和小鼠--中迅速减少分枝杆菌。我们简要介绍了药物的性质，包括其出色的杀菌活性，其作用靶点和作用机制(转位酶I)，以及我们迄今在开发口服制剂方面所做的努力。在这个第二阶段的提案中，我们概述了下一步的工作，以确定用于口服治疗方案的具有商业可行性的SQ641口服制剂(S)和有可能创造新治疗范式的注射外制剂(S)；在诊断时给予单次注射。与目前的结核病护理标准相比，这两种制剂和相关的治疗方案都将极大地迅速减少组织中的细菌，并极大地缩短和改善结核病治疗时间。异烟肼可快速杀灭感染组织中迅速复制的结核分枝杆菌(MTB)，并能减少肺部分泌物中的感染菌数量，因此被用作结核病治疗的基石药物。正如早期杀菌活性(EBA)临床研究所证明的那样，异烟肼显然是目前所有可用的结核病药物中最有效的。有趣的是，与SQ641相比，异烟肼在体外是一种相对缓慢的药物，需要几天时间才能杀死结核分枝杆菌，并且抗生素后效应(PAE)只有17小时。基于相对较短的半衰期，该药物每天给药。尽管每天给药，但最近的研究表明，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。暴露于异烟肼48小时后，~10%的结核分枝杆菌被杀死，但形态完好。相比之下，SQ641在这一时间段内杀死了90%的结核杆菌，细菌被裂解(液体培养是透明的)。此外，SQ641的PAE为55小时，是INH PAE的3倍。防止耐药性的最好方法是在细菌有机会适应药物的存在之前迅速采取行动。SQ641在体外高效地防止耐药突变的发展，并在体外与几种抗结核药物：乙胺丁醇(EMB)、链霉素和新塞克拉药物SQ109具有显著的协同活性。SQ641对药物敏感和耐多药结核分枝杆菌、甘肃分枝杆菌、脓肿分枝杆菌和禽类分枝杆菌具有良好的体外抗菌活性，也可用于治疗非结核分枝杆菌(NTM)疾病。尽管SQ641对分枝杆菌具有显著的抗菌活性，但寻找一种实用的方法来传递这种药物仍然是一个挑战。我们发现，SQ641激活了巨噬细胞中的P-糖蛋白(P-gp)药物外排泵，因此不会在感染哺乳动物的这些携带结核杆菌的重要细胞内积聚到杀菌浓度。正如预期的那样，P-gp外排抑制剂显著增强了SQ641对细胞内MTB的活性；SQ641与INH(本试验系统中最有效的单一药物)相当或更好。在小鼠中，口服SQ641吸收不良。由于许多原因(患者可接受性、方便性和成本)，口服给药是实施结核病治疗的首选方法。较差的生物利用度加上巨噬细胞的快速外流，意味着创造性地考虑药物输送。幸运的是，我们通过将SQ641和TPGS结合起来解决了药物外排和不溶性问题，TPGS是一种维生素E类似物，通常用于改善药物的溶解度，从而提高生物利用度(Eastman And Company 2005)。构建了稳定的、4-6M(~分枝杆菌大小)的SQ641-TPGS颗粒。这些颗粒很容易被巨噬细胞吞噬，SQ641在吞噬体内释放，从而有效地杀死细胞内的结核分枝杆菌。在巨噬细胞和小鼠结核病模型中，SQ641/TPGS制剂与异烟肼一样有效。在这个第二阶段的方案中，我们将评估各种方法(通过化学修饰来提高溶解度、改变药物与P-gp的相互作用，以及开发合适的商业递送系统)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剂是否可以口服(与目前的标准治疗结核病药物相结合，或作为一种或多种这些药物的替代品)和/或是否应该非肠道给药，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。