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: 8714556
• 负责人: Michelle M. Butler
• 金额: $ 100万
• 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/8714556
• 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 Resistant Tuberculosis; Drug-sensitive; Ethambutol; Exhibits; Extreme drug resistant tuberculosis; FDA approved; Feedback; Fluoroquinolones; GMP lots; Goals; HIV; 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; 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; public health relevance; 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（由申请人提供）：该项目的总体目标是开发一种新型化学类别的结核病（TB）治疗剂，即壮观酰胺系列，用于对抗结核分枝杆菌（Mtb）的MDR和XDR菌株，并通过一系列体内功效测定和临床前药代动力学、毒理学和安全药理学研究确定临床候选药物。结核病是一种致命的传染病，是仅次于艾滋病毒/艾滋病的第二大死因。世界卫生组织的估计显示，世界上三分之一的人口感染了结核分枝杆菌（Mtb），这种细菌会引起结核病；大约 10% 的感染者会在一生中的某个时期患上活动性结核病。最近令人担忧的是，涉及多重耐药 (MDR) 菌株的结核病病例数量不断增加，多重耐药菌株被定义为对异烟肼和利福平（T 疗法的两种一线抗生素）治疗具有耐药性，以及广泛耐药结核病 [XDR TB;定义为对异烟肼和利福平（对于耐多药结核病）以及任何氟喹诺酮类药物和三种注射二线药物（即阿米卡星、卡那霉素或卷曲霉素）中的至少一种具有耐药性]。耐多药/广泛耐药结核病的治疗选择包括剩下的两种一线药物，乙胺丁醇和吡嗪酰胺，菌株不耐药的二线药物，如链霉素，以及未经证实的药物，如利奈唑胺、阿莫西林/克拉维酸、克拉霉素、氯法齐明和亚胺培南。研究表明，要成功治疗广泛耐药结核病，可能需要至少四种药物和 18-24 个月的治疗时间；然而，药物的毒性可能会妨碍患者得到有效治疗。对于用于治疗耐多药/广泛耐药结核病的有效且安全的药物的医疗需求显然尚未得到满足。正如该项目第一阶段所证明的那样，新型大观霉素类似物和临床前候选药物 Lee 1599 具有针对 MDR/XDR TB 的有效体外活性（MIC90 1.2 µg/mL），在结核感染的急性和亚急性小鼠模型中均显示出功效，并且是一种安全的化合物，表现出较低的体外细胞毒性，并且未观察到体内毒性。这些总体特征主张该化合物作为耐药结核病的安全替代疗法的快速发展。在第二阶段，我们将与我们的合作者一起，博士。 Richard Lee 和 Anne Lenaerts 继续评估小鼠的体内功效（联合试验、预防复发的能力以及在慢性感染模型中的功效）。然后，我们将在两个物种中进行药代动力学研究、GLP 毒理学和安全药理学研究以及最终工艺化学研究，从而生产 GMP 批次材料。最后，我们将安排与 FDA 举行 IND 前会议，为 IND 备案做准备。在第三阶段，我们将满足所有剩余的 FDA 要求，继续探索替代给药途径，如静脉注射、肌肉注射和吸入，撰写 IND 申请并启动 I 期临床试验。