Novel spectinamide antibiotics for the treatment of MDR/XDR tuberculosis

用于治疗 MDR/XDR 结核病的新型大观酰胺抗生素

• 批准号: 8857368
• 负责人: Michelle M. Butler
• 金额: $ 98.83万
• 依托单位: MICROBIOTIX, INC
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8857368
• 关键词: AIDS/HIV problem; Acute; Adverse effects; Advocate; Aerosols; Amikacin; Aminoglycosides; Amoxicillin; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antimycobacterial Agents; Antitubercular Agents; Bacteria; Bacterial Proteins; Binding; Biological Assay; Biological Factors; Capromycin; Cause of Death; Cell Line; Cells; Cessation of life; Characteristics; Chemicals; Chemistry; Chronic; Clarithromycin; Clavulanate; Clinical; Clinical Research; Collaborations; Colorado; Communicable Diseases; Data; Death Rate; Developing Countries; Development; Development Plans; Drug Combinations; Drug Formulations; Drug Kinetics; Drug resistance in tuberculosis; Drug-sensitive; Ethambutol; Exhibits; Extreme drug resistant tuberculosis; FDA approved; Feedback; Fluoroquinolones; GMP lots; Goals; HIV; Health; Human; Imipenem; Immunocompromised Host; In Vitro; Incidence; Individual; Infection; Injectable; Interferon Type II; Intramuscular; Intravenous; Kanamycin; Knock-out; Linezolid; Mammals; Medical; Modeling; Modification; Molecular Weight; Moxifloxacin; Multi-Drug Resistance; Multidrug-Resistant Tuberculosis; Mus; Mycobacterium tuberculosis; Neisseria gonorrhoeae; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Phase I Clinical Trials; Population; Preparation; Process; Production; Protein Biosynthesis; Protein Synthesis Inhibition; Pyrazinamide; Recurrence; Relapse; Research; Research Project Grants; Resistance; Ribosomes; Rifampin; Route; Safety; Saint Jude Children' s Research Hospital; Schedule; Series; Site; Spectinomycin; Staging; Streptomycin; Therapeutic Agents; Time; Toxic effect; Toxicology; Treatment Protocols; Tuberculosis; Universities; Virulent; Withholding Treatment; World Health Organization; Writing; alternative treatment; analog; base; co-infection; compliance behavior; cytotoxicity; disorder later incidence prevention; drug discovery; improved; in vitro activity; in vivo; isoniazid; meetings; member; novel; pathogen; phase 2 study; pre-clinical; preclinical study; resistant strain; scaffold; subcutaneous; treatment duration; tuberculosis treatment

DESCRIPTION (provided by applicant): The overall objective of this project is to develop a novel chemical class of tuberculosis (TB) therapeutic agents, the spectinamide series, for use against MDR and XDR strains of Mycobacterium tuberculosis (Mtb) and identify, through a series of in vivo efficacy assays and preclinical pharmacokinetics, toxicology and safety pharmacology studies, a clinical candidate. TB is a lethal infectious disease, second only to HIV/AIDS as a cause of death. Estimates by the World Health Organization show one-third of the world population is infected with Mtb, the bacterium that causes TB; approximately 10% of infected individuals will develop active TB at some time in their lives. Of recent concern is the rising number of TB cases involving strains that are multidrug-resistant (MDR), which is defined as being resistant to treatment with isoniazid and rifampicin, the two first-line antibiotics for T therapy and those that are extensively drug-resistant tuberculosis [XDR TB; defined as being resistant to isoniazid and rifampicin (as for MDR TB) and also to any fluoroquinolone and at least one of the three injectable second-line drugs (i.e., amikacin, kanamycin, or capreomycin)]. Treatment options for MDR/XDR TB include the two remaining first-line agents, ethambutol and pyrazinamide, second- line agents to which the strain is not resistant, such as streptomycin, as well as unproven agents such as linezolid, amoxicillin/clavulanate, clarithromycin, clofazimine and imipenem. Research suggests that at least four drugs and 18-24 month duration of treatment may be required for successful therapy of XDR TB; however, toxicity of the agents may preclude patients from being effectively treated. There is a clear unmet medical need for efficacious and safe drugs to be used as treatment for MDR/XDR TB. As demonstrated in Phase I of the project, the novel spectinomycin analog and preclinical candidate, Lee 1599, possesses potent in vitro activity against MDR/XDR TB (MIC90 1.2 �g/mL), demonstrates efficacy in both acute and subacute murine models of TB infection, and is a safe compound, displaying low in vitro cytotoxicity and no observed in vivo toxicity. These overall characteristic advocate for the rapid development of this compound as a safe alternative treatment for drug resistant TB. In Phase II, we will, in conjunction with our collaborators, Drs. Richard Lee and Anne Lenaerts, continue to evaluate in vivo efficacy in mice (combination trials, ability to preven recurrence and efficacy in a chronic infection model). We will then conduct pharmacokinetic studies, GLP toxicology and safety pharmacology studies in two species as well as final process chemistry, leading to manufacturing of a GMP lot of material. Finally, we will schedule a pre-IND meeting with the FDA in preparation for an IND filing. In Phase III, we will meet all remaining FDA requirements, continue to explore alternative routes of administration such as intravenous, intramuscular and inhalational, write an IND application and initiate Phase I clinical trials.

描述（由适用提供）：该项目的总体目标是开发一种新型的结核病（TB）治疗剂，Spotinamide系列，用于对结核分枝杆菌（MTB）的MDR和XDR菌株的使用，并通过一系列的体内效率评估和预先研究的候选药物学和预先研究，并识别出一系列的效率效率评估和临床疗法。结核病是一种致命的传染病，仅次于艾滋病毒/艾滋病作为死亡原因。世界卫生组织的估计显示，世界人口的三分之一被MTB感染，MTB是导致结核病的细菌。大约10％的受感染者将在他们的生活中某个时候发展活跃的结核病。最近关注的是，涉及多种耐药性（MDR）的TB病例数量增加，该菌株被定义为具有Isoniazid和Rifampicin的耐药性，这是两种用于T疗法的一线抗生素，以及那些广泛的药物耐药性结核病[XDR TB；被定义为对异烟肼和利福平（如MDR TB）的耐药性，也对任何氟喹诺酮类药物以及至少三种可注射二线药物（即amikacin，kanamycin或capreomycin）中的至少一种。 MDR/XDR TB的治疗选择包括剩余的两条一线剂，乙酰丁醇和吡嗪酰胺，二线剂，菌株不具有抗性，例如链霉素，以及未经证实的药物，例如linezolid，如linezolid，阿莫氧基霉素/氯三酸酯/氯酸酯，Clarithromycin，clithithromycin，clithithromycin，clofazimine，clofazimine，climipipazimine和imipipenemenemenement。研究表明，成功治疗XDR TB可能需要至少四种药物和18-24个月的治疗时间。但是，药物的毒性可能阻止患者有效治疗。对于MDR/XDR TB的治疗，对有效且安全的药物有明显的未满足医疗需求。如该项目的第一阶段所证明的那样，新型Spectinomycin类似物和临床前候选者Lee 1599，潜在的潜在的对MDR/XDR TB的体外活性（MIC90 1.2.G/ML）表明，TB感染的急性和亚急性鼠模型都表现出效率，并且表现出对毒素的安全性，并且对毒素的效率不足，并且没有效率。这些总体特征倡导这种化合物作为耐药结核病的安全替代方法。在第二阶段，我们将与我们的合作者Drs一起。理查德·李（Richard Lee）和安妮·莱纳特（Anne Lenaerts）继续评估小鼠体内效率（联合试验，预防慢性感染模型中复发和效率的能力）。然后，我们将对两种物种以及最终过程化学进行药代动力学研究，GLP毒理学和安全药理学研究，从而导致GMP大量材料的生产。最后，我们将安排与FDA的预定会议，以准备IND申请。在第三阶段中，我们将满足所有剩余的FDA要求，继续探索静脉内，肌肉内和意外的替代行政途径，撰写IND应用并开始I期临床试验。