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进一步开发一种新型化学类别的结核病(TB)治疗剂--spectinamide系列，用于对抗结核分枝杆菌(Mtb)的MDR和XDR菌株，并通过一系列体外和体内试验确定临床前候选药物。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，涉及多药耐药(MDR)菌株的结核病病例不断增加，耐多药菌株的定义是耐异烟肼和利福平，这两种抗生素是结核病治疗的两种一线抗生素，而广泛耐药结核病[XDR TB；定义为对异烟肼和利福平耐药(与耐多药结核病一样)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。新的壮观霉素类似物对MDR/XDR TB具有较强的体外抗MDR/XDR TB活性(MIC 0.4~1.6 5g/mL)，通过杀菌作用机制发挥作用，具有进入巨噬细胞的能力，是结核感染的宿主部位，是安全的化合物，体外细胞毒性低，体内没有观察到的毒性。这些总体特征促使这些化合物迅速发展，成为治疗耐药结核病的安全替代疗法。我们将与我们的合作者Richard Lee博士和Helena Boshoff博士一起研究spectinide类别的体外特性，包括对MDR/XDR TB分离株的效力、对哺乳动物细胞系的最低毒性和代谢稳定性。然后，我们将扩大最有利于体内研究的类似物的合成，并在此过程中优化合成化学路线。最后，我们将与安妮·勒纳尔茨博士合作，在小鼠身上评估体内毒理学、药代动力学和疗效。这些实验将使我们能够确定适合进入第二阶段的最终先导和后备化合物。在第二阶段，我们将对临床前候选药物进行长期体内疗效研究，无论是作为单一疗法还是与抗结核药物联合治疗耐多药结核病。我们还将进行药代动力学研究、GLP毒理学和安全药理学研究，以选择适合IND提交的最终抗MDR/XDR临床候选药物。

DESCRIPTION (provided by applicant): The overall objective of this project is to further 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 vitro and in vivo assays, a preclinical 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 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. The novel spectinomycin analogs outlined in this proposal possess potent in vitro activity against MDR/XDR TB (MIC 0.4-1.6 5g/mL), act via a bactericidal mechanism of action, have demonstrated ability to enter macrophages, the host location of TB infections, and are safe compounds, displaying low in vitro cytotoxicity and no observed in vivo toxicity. These overall characteristics advocate for the rapid development of these compounds as a safe alternative treatment for drug resistant TB. We will, in conjunction with our collaborators, Dr. Richard Lee and Helena Boshoff, characterize the in vitro properties of the spectinamide class, including potency against MDR/XDR TB isolates, minimum toxicity against mammalian cell lines and metabolic stability. We will, then scale-up the synthesis of the most favorable analogs for in vivo studies and optimize the synthetic chemistry route in the process. Finally, in collaboration with Dr. Anne Lenaerts, we will evaluate in vivo toxicology, pharmacokinetics and efficacy in mice. These experiments will allow us to identify a final lead and backup compound suitable for advancement to Phase II. In Phase II, we will conduct long term in vivo efficacy studies of the preclinical candidate, both as monotherapy and in combination with anti-TB agents for MDR-TB. We will also conduct pharmacokinetic studies, GLP toxicology and safety pharmacology studies to select a final anti-MDR/XDR clinical candidate suitable for IND submission.