Investigation of synergy between Rifampin and SQ109, a new anti-TB drug candidate

利福平与新型抗结核候选药物SQ109之间的协同作用研究

• 批准号: 7489360
• 负责人: VENKATA M REDDY
• 金额: $ 20.23万
• 依托单位: SEQUELLA, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7489360
• 关键词: Adverse effects; Anabolism; Animals; Antibiotics; Antitubercular Agents; Appendix; Applications Grants; Area; Biological; Biological Assay; Biotechnology; Cell Wall; Characteristics; Chemicals; Clinical Trials; Collaborations; Combination Chemotherapy; Combination Drug Therapy; Combined Modality Therapy; Condition; Cytochrome P450; Data; Developed Countries; Developing Countries; Development; Diamines; Disease; Dose; Drug Compounding; Drug Interactions; Drug Kinetics; Drug Metabolic Detoxication; Drug resistance in tuberculosis; Drug toxicity; Enzymes; Ethambutol; Failure; Fatty Acids; Frequencies; Future; Genes; Genetic Transcription; Genus Mycobacterium; Grant; Growth; HIV; Heme; Human; Human Volunteers; Immunosuppression; In Vitro; Individual; Infection; Investigation; Knock-out; Knowledge; Lead; Libraries; Link; Liver Microsomes; Lung; Malnutrition; Mammalian Cell; Manuscripts; Mass Spectrum Analysis; Mediating; Metabolism; Modeling; Multi-Drug Resistance; Multidrug-Resistant Tuberculosis; Mus; Mycobacterium tuberculosis; Oral; Pharmaceutical Preparations; Pharmacodynamics; Phase; Play; Principal Investigator; Production; Property; Proteins; Public Health; Pulmonary Tuberculosis; Pyrazinamide; Rate; Reaction; Resistance; Respiratory System; Rifampin; Role; Standards of Weights and Measures; Steroids; Sterols; Structure; Testing; Therapeutic; Therapeutic immunosuppression; Time; Tissues; Treatment Protocols; Tuberculosis; Work; World Health Organization; Xenobiotics; bactericide; cytotoxicity; design; drug standard; in vitro Assay; in vivo; interest; isoniazid; killings; macrophage; mortality; mouse model; mutant; novel diagnostics; pre-clinical; preclinical study; prevent; programs; research and development; research study; tool; treatment duration; tuberculosis drugs; tuberculosis treatment

DESCRIPTION (provided by applicant): SQ109 is a new anti-TB drug candidate that is currently undergoing Phase Ia Clinical Trials in humans. SQ109 was selected out of the library of 63,238 compounds, because it is highly efficacious in killing M. tuberculosis within infected macrophages and in experimental animals, has relatively low cytotoxicity in cultured mammalian cells, has activity against both drug-susceptible and drug-resistant M. tuberculosis, and has drug-like pharmacokinetic and pharmacodynamic profiles. Any new anti-TB drug will be used in combination with other drugs in order to prevent the emergence of drug resistant M. tuberculosis. How SQ109, a new drug compound with unique attributes, interacts with existing first line anti-TB drugs is crucial for us to understand, as this knowledge enables us to design the most efficacious therapeutic combination and to avoid any antagonistic side effects of a new combination therapy. We investigated the drug interaction in various combinations of SQ109 with the first line anti-TB drugs in both in vitro assays and in vivo murine models of TB. We found that SQ109 preferentially synergized with RIF in in vitro growth inhibition assays and demonstrated enhanced bactericidal activity in mice when used in combination with INH and RIF. These findings are significant for optimizing the drug combination therapies to be tested in future clinical trials. In this exploratory R21 grant Application we will: 1. Assess whether SQ109 is metabolized within M. tuberculosis and how co-administration of RIF influences SQ109 metabolism. If SQ109 metabolites exist, we will study their structures by mass spectrometry and will compare them to the SQ109 metabolites generated by human CYP. If the metabolites are the same, we will prepare and purify them in sufficient quantities and test them against M. tuberculosis for potency in vitro. 2. Determine the expression of individual CYP in RIF-treated M. tuberculosis in order to identify candidate SQ109 activators that are induced by RIF. 3. Generate M. tuberculosis knock out mutants of the candidate CYP(s) and re-examine the synergy of interaction between SQ109 and RIF in the CYP knockout mutants. Public Health Relevance: One of the most vexing problems with standard tuberculosis (TB) therapy is the lengthy treatment course (6-9 months) and toxicity of the drugs in the regiment. This prolonged therapeutic regimen results in a high level of noncompliance, and ineffective concentrations of drugs lead to the emergence of multidrug resistant (MDR) M. tuberculosis. There are an estimated 400,000 new cases of MDR TB each year, and the World Health Organization (WHO) estimates there are 50 million individuals worldwide infected with a resistant strain of TB. MDR strains of M. tuberculosis cause increased mortality, and the fatality rate of untreated cases of MDR TB can be as high as 70%. The likelihood of cure for MDR M. tuberculosis-infected individuals becomes even less in the setting of secondary immunosuppression caused by HIV and malnutrition, conditions that are rampant in developing countries. Because of the failures of the existing therapies, the world desperately needs new drugs that can shorten treatment duration and kill MDR M. tuberculosis. Sequella, Inc., founded in 1997, focuses its R&D on developing new diagnostic tools and new drugs for TB disease. One of our most successful projects is the development of SQ109, a new anti-TB drug candidate that is currently undergoing Phase Ia Clinical Trials. SQ109 was selected as our lead drug candidate out of the library of 63,238 compounds, because it is highly efficacious in killing M. tuberculosis within infected macrophages and in experimental animals, has relatively low cytotoxicity in cultured mammalian cells, has activity against both drug-susceptible and drug-resistant M. tuberculosis, and has drug-like pharmacokinetic and pharmacodynamic profiles. Importantly, when used in combination with rifampin (RIF) + isoniazid (INH) + pyrazinamide (PZA), SQ109 is able to increase bacterial killing and reduce the time by at least 25% to achieve the same level of CFU as the standard drug regimen, RIF + INH + PZA + ethambutol (EMB) in a mouse model of TB. Any new anti-TB drug will be used in combination with other drugs in order to prevent the emergence of drug resistant M. tuberculosis. How SQ109, a new drug compound with unique attributes, interacts with existing first line anti-TB drugs is crucial for us to understand, as this knowledge enables us to design the most efficacious therapeutic combination and to avoid any antagonistic side effects of a new combination therapy. In this R21 exploratory grant application, we propose to investigate one of the several hypotheses that may contribute to the synergistic interaction between SQ109 and RIF in M. tuberculosis: (1) SQ109 is readily metabolized in M. tuberculosis, (2) RIF is able to induce the expression of one or more M. tuberculosis CYP- like proteins, and (3) CYP induced by RIF is involved in SQ109 metabolism. Tasks 1 and 2 are two independent areas of study, which are linked by task 3. In this application, we outline the experiment design for all three tasks in sequence. Further, we provide alternative directions for the study of this interesting synergy if the data obtained do not support our hypothesis.

描述（申请人提供）：SQ 109是一种新的抗结核候选药物，目前正在进行人体Ia期临床试验。SQ 109是从63，238种化合物的库中选出的，因为它在杀死M.结核分枝杆菌在感染的巨噬细胞内和实验动物中具有相对低的细胞毒性，在培养的哺乳动物细胞中具有抗药物敏感和耐药M.结核病，并具有药物样药代动力学和药效学特征。任何新的抗结核药物都将与其他药物联合使用，以防止耐药M的出现。结核SQ 109是一种具有独特属性的新药化合物，如何与现有的一线抗结核药物相互作用对我们来说至关重要，因为这一知识使我们能够设计最有效的治疗组合，并避免新组合疗法的任何拮抗副作用。我们在体外试验和体内TB鼠模型中研究了SQ 109与一线抗TB药物的各种组合中的药物相互作用。我们发现SQ 109在体外生长抑制试验中优先与RIF协同作用，并且当与INH和RIF组合使用时，在小鼠中显示出增强的杀菌活性。这些发现对于优化未来临床试验中要测试的药物组合疗法具有重要意义。在这个探索性的R21补助金申请，我们将：1。评估SQ 109是否在M内代谢。以及RIF联合给药如何影响SQ 109代谢。如果存在SQ 109代谢物，我们将通过质谱法研究其结构，并将其与人大肠杆菌产生的SQ 109代谢物进行比较。如果代谢物相同，我们将制备并纯化足够数量的代谢物，并检测其对M的抑制作用。结核病的体外效力。2.测定RIF处理的M细胞中单个mRNA的表达。为了鉴定由RIF诱导的候选SQ 109激活剂，对结核病进行了研究。3.生成M。结核病敲除候选RIF的突变体，并重新检查SQ 109和RIF在RIF敲除突变体中的相互作用的协同作用。 公共卫生相关性：标准结核病（TB）治疗最令人烦恼的问题之一是治疗过程漫长（6-9个月）和药物毒性。这种延长的治疗方案导致高水平的不依从性，并且无效的药物浓度导致多药耐药（MDR）M的出现。结核据估计，每年有40万例新的耐多药结核病病例，世界卫生组织（WHO）估计，全世界有5000万人感染了耐药结核病菌株。耐药株M.结核病导致死亡率增加，未经治疗的耐多药结核病病例的死亡率可高达70%。MDR M治愈的可能性。在发展中国家普遍存在的艾滋病毒和营养不良引起的继发性免疫抑制的情况下，结核病感染者的死亡率甚至更低。 由于现有疗法的失败，世界迫切需要新的药物，可以缩短治疗时间和杀死MDR M。结核Sequella，Inc.该公司成立于1997年，其研发重点是开发新的结核病诊断工具和新药。我们最成功的项目之一是开发SQ 109，这是一种新的抗结核候选药物，目前正在进行Ia期临床试验。SQ 109从63，238种化合物的库中被选为我们的主要候选药物，因为它在杀死M.结核分枝杆菌在感染的巨噬细胞内和实验动物中具有相对低的细胞毒性，在培养的哺乳动物细胞中具有抗药物敏感和耐药M.结核病，并具有药物样药代动力学和药效学特征。重要的是，当与利福平（RIF）+异烟肼（INH）+吡嗪酰胺（PZA）组合使用时，SQ 109能够增加细菌杀灭并将时间减少至少25%，以在TB小鼠模型中实现与标准药物方案RIF + INH + PZA +乙胺丁醇（EMB）相同的CFU水平。 任何新的抗结核药物都将与其他药物联合使用，以防止耐药M的出现。结核SQ 109是一种具有独特属性的新药化合物，如何与现有的一线抗结核药物相互作用对我们来说至关重要，因为这一知识使我们能够设计最有效的治疗组合，并避免新组合疗法的任何拮抗副作用。 在R21探索性资助申请中，我们提出了几个可能有助于SQ 109和RIF在M中协同相互作用的假设之一。结核分枝杆菌：（1）SQ 109在M.（2）RIF能够诱导一种或多种M. RIF介导的肺结核病毒感染与SQ 109代谢有关。任务1和2是两个独立的研究领域，由任务3联系起来。在这个应用程序中，我们概述了所有三个任务的实验设计顺序。此外，如果获得的数据不支持我们的假设，我们提供了这种有趣的协同作用的研究的替代方向。