Development of Novel Proteins Synthesis Inhibitors for MDR Tuberculosis

摘要 为了应对耐多药结核病的出现和传播，一种新的半合成 一系列壮观霉素类似物是通过细菌选择性核糖体抑制和 具有优异的窄谱抗结核活性。这些类似物，壮观的酰胺，缺乏交叉- 抵抗现有的结核病治疗方法，保持对MDR-和XDR-的活性 结核，保留壮观霉素的高选择性指数，并协同减少肺部细菌 与其他结核病疗法联合使用时，慢性活体小鼠模型的负担。这个 壮观胺强大的抗结核和选择性特性是因为它们有能力避免 Rv1258c泵的固有外排，表明对经典的合成修改 抗生素可以克服内在外排泵介导的耐药性的挑战。详细的SAR 已被开发用于蛋白质合成抑制和外排避免，药代动力学，以及 壮观胺类药物的体内疗效。最显著的结果是观察到的协同效应 壮观酰胺与利福平、吡津胺合用治疗C3HeB/FEJ小鼠结节 与人类发现的病变相似的病变。在这次更新中，我们的目标是专注于 协同增效的壮观酰胺类药物的研究进展 其他结核制剂通过3个迭代目标清除坏死性病变中的感染：(I)联合 学习。这一目标的目标是评估和定义壮观胺联合治疗 特别针对坏死性肉芽肿中的协同活性。(Ii)第二代 一代抗结核壮观霉素类似物。下一代的设计与合成 壮观霉素抗结核抗生素的主要目标是增加治疗 通过改善宿主耐受性、生物利用度、分布到 肉芽肿，并避免外流。(3)对第二代壮观酰胺的评价-- 在AIM 2中合成的化合物将通过三个迭代阶段的测试，包括 微生物评价、药代动力学试验、毒理学和体内药效试验。

Abstract To address the emergence and spread of multi‐drug resistant tuberculosis, a novel semisynthetic series of spectinomycin analogs was generated with bacterial selective ribosomal inhibition and excellent narrow‐spectrum antitubercular activity. These analogs, the spectinamides, lack cross‐ resistance with existing tuberculosis therapeutics, maintain activity against MDR‐ and XDR‐ tuberculosis, retain spectinomycin’s high selectivity index, and synergistically reduce lung bacterial burdens in chronic in vivo mouse models when used in combination with other TB therapies. The potent antitubercular and selective properties of spectinamides is the result of their ability to avoid intrinsic efflux by the Rv1258c pump, demonstrating that synthetic modifications to classical antibiotics can overcome the challenge of intrinsic efflux pump‐mediated resistance. Detailed SAR has been developed for protein synthesis inhibition and efflux avoidance, pharmacokinetics, and in vivo efficacy of the spectinamides. The most notable result is the synergy observed when spectinamides are combined with rifampin and pyrazinamide in C3HeB/FeJ mice bearing tubercular lesions with similar pathology to those found in humans. In this renewal, we aim focus the development of the spectinamides as combination agents capable of working synergistically with other TB agents to clear infections in necrotic lesions through 3 iterative aims: (i) Combination studies. The goal of this aim is to evaluate and define spectinamide combination treatments that specifically target synergistic activity in the necrotic granuloma. (ii) Generation of second generation antitubercular spectinomycin analogs. The design and synthesis of the next generation of spectinomycin antitubercular antibiotics with the primary goal of increasing the therapeutic window of lead compounds via improved host tolerability, bioavailability, distribution into the granuloma, and efflux avoidance. (iii) Evaluation of second generation spectinamides – Compounds synthesized in aim 2 will progress through three iterative stages of tests that include microbial assessment, pharmacokinetic testing, toxicologic and in vivo efficacy experiments.