Novel spectinamide antibiotics for the treatment of MDR/XDR tuberculosis

项目描述（由申请人提供）：该项目的总体目标是开发一种新的化学类结核病治疗药物，即spectinamide系列，用于治疗耐多药和广泛耐药结核分枝杆菌（Mtb）菌株，并通过一系列体内疗效试验、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。据世界卫生组织估计，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发展为活动性结核病。最近令人关切的是，涉及耐多药菌株的结核病病例数量不断增加，耐多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）和广泛耐药结核病(XDR TB；定义为对异烟肼和利福平（如耐多药结核病）以及任何氟喹诺酮类药物和三种可注射二线药物（即阿米卡星、卡那霉素或卷曲霉素）中的至少一种具有耐药性。耐多药/广泛耐药结核病的治疗方案包括剩余的两种一线药物，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，药物的毒性可能使患者无法得到有效治疗。用于治疗耐多药/广泛耐药结核病的有效和安全药物的医疗需求显然未得到满足。正如该项目的I期所证明的那样，新型大霉素类似物和临床前候选物Lee 1599具有抗MDR/XDR结核病的有效体外活性（MIC90 1.2 μ g/mL），在急性和亚急性小鼠结核感染模型中均有效，并且是一种安全的化合物，显示出低的体外细胞毒性和未观察到的体内毒性。这些总体特征主张迅速开发这种化合物，作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，dr。Richard Lee和Anne Lenaerts继续在小鼠体内评估疗效（联合试验、预防复发的能力和慢性感染模型的疗效）。然后，我们将在两种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的工艺化学，从而生产出符合GMP要求的大量材料。最后，我们将与FDA安排IND前会议，为IND申请做准备。在III期，我们将满足所有剩余的FDA要求，继续探索其他给药途径，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。

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.