Novel Spectinamide Antibiotics for the Treatment of MDR/XDR Tuberculosis

摘要/摘要 该项目的总体目标是开发一种新的化学类结核病(TB)疗法。 抗结核分枝杆菌多药耐药和XDR菌株(结核分枝杆菌)和 通过一系列体内疗效分析和临床前药代动力学，确定毒理学和安全性 药理学专业，临床考生。结核病是一种致命的传染病，是仅次于艾滋病毒/艾滋病的 死因是。世界卫生组织的估计显示，世界上四分之一的人口受到感染 结核分枝杆菌是一种引起结核病的细菌；大约10%的感染者在某些情况下会发展为活动性结核病 他们生命中的时间。最近令人担忧的是，涉及多种药物菌株的结核病病例数量不断增加。 耐药(MDR)，定义为对异烟肼和利福平这两个一线药物的治疗耐药 治疗结核病的抗生素和广泛耐药的结核病[广泛耐药结核病；定义为 对异烟肼和利福平(对于耐多药结核病)以及对任何氟喹诺酮类药物和至少一种 三种可注射二线药物(即阿米卡星、卡那霉素或卷曲霉素)]。治疗方案的选择 MDR/XDR TB包括剩下的两种一线药物乙胺丁醇和吡嗪酰胺，这两种二线药物用于 这种菌株不耐药，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，至少有四种药物 而成功治疗广泛耐药结核可能需要18-24个月的疗程；然而， 这些药物可能会使患者无法得到有效的治疗。显然，有一种未得到满足的医疗需求 治疗耐多药/广泛耐药结核的有效和安全的药物。正如项目第一阶段所展示的那样， 新的壮观霉素类似物和关键的壮观酰胺类化合物具有强大的体外抗MDR/XDR TB活性， 在急性和亚急性结核病感染的小鼠模型中都显示出有效性，是安全的化合物， 体外细胞毒性低，未观察到体内毒性。在第二阶段，我们确定MBX 4888是 临床前候选药物，具有与其他先导化合物相似的疗效，但安全性更好。同相 IIB，我们将与我们的合作者理查德·李博士、格雷格·罗伯逊博士和安妮·勒纳尔茨博士继续 评价其在小鼠体内的药效(吸入剂量)。我们还将进行药代动力学研究，GLP 两个物种的毒理学和安全性药理学研究以及非GMP和GMP批次的生产 足够完成临床前和第一阶段临床研究的材料。最后，我们将安排一次预试 与FDA和南非当局会面，为IND申请做准备。在第三阶段，我们将 所有剩余的FDA要求，继续探索替代给药途径，如吸入， 编写IND应用程序并启动I期临床试验。这些总体特征倡导快速的 开发MBX 4888作为耐药结核病的安全替代疗法。

Summary/Abstract 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-quarter 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 TB 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 key spectinamides, possess potent in vitro activity against MDR/XDR TB, demonstrate efficacy in both acute and subacute murine models of TB infection, and are safe compounds, displaying low in vitro cytotoxicity and no observed in vivo toxicity. In Phase II, we identified MBX 4888 as the preclinical candidate, with similar efficacy to other lead compounds but with an improved safety profile. In Phase IIb, we will, in conjunction with our collaborators, Drs. Richard Lee, Greg Robertson and Anne Lenaerts, continue to evaluate in vivo efficacy in mice (inhalational dosing). We will also conduct pharmacokinetic studies, GLP toxicology and safety pharmacology studies in two species as well as manufacturing of non-GMP and GMP lots of material sufficient to complete preclinical and Phase I clinical studies. Finally, we will schedule a pre-IND meeting with the FDA and the South African authorities 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 inhalational, write an IND application and initiate Phase I clinical trials. These overall characteristics advocate for the rapid development of MBX 4888 as a safe alternative treatment for drug resistant TB.