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: 7299884
• 负责人: VENKATA M REDDY
• 金额: $ 24.75万
• 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 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7299884
• 关键词: Adverse effects; Anabolism; Animals; Antibiotics; Antitubercular Agents; Appendix; Applications Grants; Area; Bacteria; 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; Enzyme Activation; Enzymes; Ethambutol; Failure; Fatty Acids; Frequencies; Future; Gene Expression; 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; Nature; Oral; Pharmaceutical Preparations; Pharmacodynamics; Phase; Play; Principal Investigator; Prodrugs; 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; base; cytotoxicity; design; drug standard; in vitro Assay; in vivo; interest; isoniazid; killings; macrophage; mortality; mouse model; mutant; mycobacterial; 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（由申请人提供）：SQ109是一种新的抗TB药物，目前正在人类中进行IA期临床试验。从63,238种化合物的库中选择了SQ109，因为它在杀死感染巨噬细胞内的结核分枝杆菌和实验性动物中具有高度有效性，在培养的哺乳动物细胞中具有相对较低的细胞毒性，在药物感染和药物耐药的肺泡型和具有药物类药物的药物含量和药物含量的药物含量且具有药物含量的药物治疗中具有相对较低的活性。任何新的抗TB药物都将与其他药物联合使用，以防止耐药性结核分枝杆菌的出现。具有独特属性的新药SQ109与现有第一行抗TB药物相互作用对我们来说至关重要，因为这些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。我们在体外测定和TB的体内鼠模型中研究了SQ109与第一线抗TB药物的各种组合中的药物相互作用。我们发现，在体外生长抑制测定中，SQ109优先与RIF协同协同，并在与INH和RIF结合使用时表现出小鼠的杀菌活性增强。这些发现对于在未来的临床试验中进行测试的药物组合疗法非常重要。在此探索性R21赠款应用中，我们将：1。评估SQ109是否在结核分枝杆菌中代谢，以及RIF的共同给药如何影响SQ109代谢。如果存在SQ109代谢物，我们将通过质谱研究其结构，并将它们与人CYP产生的SQ109代谢产物进行比较。如果代谢物是相同的，我们将用足够量的足够数量准备和净化它们，并针对结核分枝杆菌进行测试，以实现体外效力。 2。确定RIF处理的结核分枝杆菌中单个CYP的表达，以鉴定由RIF诱导的候选SQ109激活剂。 3。产生结核分枝杆菌敲除候选CYP的突变体，并重新检查CYP敲除突变体中SQ109和RIF之间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该团中药物的冗长治疗课程（6-9个月）和毒性。这种延长的治疗方案导致高水平的不符合性，无效的药物浓度导致多药耐药（MDR）肺结核分枝杆菌的出现。估计每年有40万例MDR结核病病例，世界卫生组织（WHO）估计全球有5000万个人感染了TB的抗性菌株。结核分枝杆菌的MDR菌株会导致死亡率增加，未经治疗的MDR TB病例的死亡率可能高达70％。在艾滋病毒和营养不良引起的继发性免疫抑制的情况下，MDR M.结核分枝杆菌的治疗可能性甚至更少，在发展中国家猖ramp。 由于现有疗法的失败，世界迫切需要可以缩短治疗时间并杀死MDR M.结核病的新药。 Sequella，Inc。成立于1997年，将其研发重点放在开发新的诊断工具和新药物的结核病疾病上。我们最成功的项目之一是SQ109的开发，SQ109是一种新的抗TB药物候选者，目前正在IA临床试验中。 SQ109被选为63,238种化合物库中的主要候选药物，因为它在杀死感染巨噬细胞和实验动物中杀死结核分枝杆菌的高效，在培养的哺乳动物细胞中具有相对较低的细胞毒性，因此对药物敏感和药物抗药性的药物均具有药物良好的药物良好的药物，并且具有药物治疗效率。重要的是，当与利福平（RIF） +异酮（INH） +吡嗪酰胺（PZA）结合使用时，SQ109能够增加细菌杀伤并将时间减少至少25％，以达到与标准药物方案相同的CFU，RIF + PZA + PZA + ETHAMB + ETHABB + ETHABB + ETHABB + ETHABB + EMBARBUTOL（emb） 任何新的抗TB药物都将与其他药物联合使用，以防止耐药性结核分枝杆菌的出现。具有独特属性的新药SQ109与现有第一行抗TB药物相互作用对我们来说至关重要，因为这些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。 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代谢。任务1和2是两个独立的研究领域，这些领域由任务3链接。在本应用程序中，我们概述了所有三个任务的实验设计。此外，如果获得的数据不支持我们的假设，我们为研究这种有趣的协同作用提供了替代方向。