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）的医生迫切需要新的，有效的和有效的抗生素，以改善多药耐药（MDR）的治疗时间和治疗的耐用性以及无用的TB。在完成的第1阶段赠款（下面的最终报告）中，我们评估了令人兴奋的新药候选人SQ641。 SQ641的活性优于异念珠菌（INH）和所有其他结核病药物，在适当的条件下，在我们的两个最佳结核病模型中迅速降低了分枝杆菌。巨噬细胞和小鼠。我们简要描述了药物特性，包括其特殊的杀菌活性，其作用和机理（转运酶I）以及我们迄今为止开发口服配方的努力。在此第2阶段提案中，我们概述了针对口服治疗方案的SQ641的商业可行口服配方的下一步，以及肠胃外的表述，有可能创建新的治疗范式；诊断时给予一个单一的肠胃外剂量。与当前的结核病护理标准相比，配方和相关的治疗方案将大大减少组织中的细菌，并大幅缩短并改善了结核病治疗时间。 INH被用作第2个强化化学疗法作为结核病治疗的基石药物，因为它能够迅速杀死感染组织中迅速复制结核分枝杆菌（MTB）并减少肺部分泌中传染性细菌的数量。正如早期杀菌活性（EBA）临床研究所证明的那样，INH显然是当前所有可用的结核病药物中最有效的。有趣的是，与SQ641相比，INH是一种相对较慢的药物，需要几天杀死MTB，并且抗生素后效应（PAE）仅为17小时。根据相对较短的半衰期，该药物每天服用。尽管每天给药，但最近的研究表明，可行细菌的数量仍然足以促进生理学（Siddiqi等，2007）和耐基因型药物。接触INH 48小时后，约有10％的MTB被杀，但在形态上仍然完好无损。相比之下，SQ641在这段时间内杀死了90％的MTB，并且细菌是裂解的（液态培养很明显）。此外，SQ641的PAE为55小时，是INH PAE的3倍。预防耐药性的最佳方法是在细菌有机会适应该药物的存在之前迅速采取行动。 SQ641在预防体外耐药突变体的发展方面非常有效，并且在体外具有协同活性，并与几种抗蛋白结核病：ethambutol（EMB），链霉菌素和新的Sequella Drug，SQ109。 SQ641具有针对药物易感性的极好的体外活性，MDB，M。Kansasii，M。Abscessus和M. avium具有出色的体外活性，也可以用于无结核的分枝杆菌（NTM）疾病。尽管SQ641对分枝杆菌具有显着的抗生素特性，但采用该药物的实际方法仍然是一个挑战。我们发现SQ641激活了巨噬细胞中的P-糖蛋白（P-GP）药物外泵，因此不会积聚到这些重要细胞内含有MTB的杀菌浓度，这些细胞内有MTB感染的哺乳动物中的MTB。正如预期的那样，P-gp外排抑制剂显着增强了SQ641对细胞内MTB的活性。 SQ641等同于或优于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。由于许多原因（患者可接受性，便利性和成本），口服分娩是管理结核病治疗的首选方法。糟糕的生物利用度与巨噬细胞的快速外排相结合，意味着创造性地思考药物输送。幸运的是，我们通过将SQ641与TPG结合在一起，解决了外排和不溶性问题，TPG是一种通常用于改善药物溶解度和生物利用度的维生素E模拟（Eastman and Company 2005）。稳定，4-6？m（〜分枝杆菌的大小）构建了含有SQ641的TPGS颗粒。这些颗粒很容易被巨噬细胞吞噬，而SQ641在吞噬体内释放，以有效地杀死细胞内MTB。在TB的巨噬细胞和小鼠模型中，SQ641/TPGs公式与INH一样有效。在此第2阶段的建议中，我们将评估各种方法（化学修饰以增强溶解度，改变药物-P-GP相互作用并开发适当的商业输送系统），以溶解SQ641并优化其在体内的递送。我们将探索制剂，以确定该有效的抗菌药物是否可以口服递送（与当前的护理标准结核病药物或其中一种或多种药物相结合）和/或应在育儿中送达TB化学疗法，并在TB治疗期间提供早期和延长细菌清除率。