Novel spectinamide antibiotics for the treatment of MDR/XDR tuberculosis

描述(由申请人提供)：该项目的总体目标是开发一种新的化学类别的结核病(TB)治疗药物--spectinide系列，用于对抗结核分枝杆菌(Mtb)的MDR和XDR菌株，并通过一系列体内疗效分析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，这种细菌会导致结核病；大约10%的感染者会在一生中的某个时候患上活动性结核病。最近令人关切的是，对异烟肼和利福平、T疗法的两种一线抗生素异烟肼和利福平以及广泛耐药结核病[XDR TB；定义为对异烟肼和利福平以及任何氟喹诺酮和至少三种可注射二线药物(即阿米卡星、卡那霉素或卷曲霉素)中的至少一种]耐药的结核病例的多药耐药病例有所增加。耐多药/广泛耐药结核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，成功治疗广泛耐药结核病可能需要至少四种药物和18-24个月的疗程；然而，这些药物的毒性可能会阻碍患者得到有效的治疗。对于用于治疗耐多药/广泛耐药结核病的有效和安全的药物，显然存在未得到满足的医疗需求。正如项目第一阶段所证明的，新型壮观霉素类似物和临床前候选药物Lee 1599具有很强的体外抗多药/广泛耐药结核活性(MIC901.2�g/mL)，在急性和亚急性结核感染小鼠模型中都显示出有效性，是一种安全的化合物，体外细胞毒性低，体内没有观察到毒性。这些总体特征促使这种化合物迅速发展，成为耐药结核病的安全替代治疗方法。在第二阶段，我们将与我们的合作者理查德·李博士和安妮·勒纳尔茨博士一起，继续评估小鼠体内的疗效(组合试验、预防复发的能力和在慢性感染模型中的有效性)。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，从而生产大量GMP材料。最后，我们将与FDA安排一次IND前会议，为IND申请做准备。在第三阶段，我们将满足FDA的所有剩余要求，继续探索静脉、肌肉和吸入等替代给药途径，编写IND应用程序，并启动第一阶段临床试验。

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.