Development of Novel Proteins Synthesis Inhibitors for MDR Tuberculosis

耐多药结核病新型蛋白质合成抑制剂的开发

• 批准号: 10353377
• 负责人: Richard E. Lee
• 金额: $ 74.77万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-06 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10353377
• 关键词: Address; Antibiotics; Antitubercular Agents; Antitubercular Antibiotics; Automobile Driving; Award; Biological Availability; Bolus Infusion; C3HeB/FeJ Mouse; Chemicals; Chronic; Combined Modality Therapy; Complement; Complex; Data; Development; Drug Kinetics; Drug Tolerance; Ensure; Environment; Evaluation; Extreme drug resistant tuberculosis; Future Generations; Generations; Goals; Granuloma; Human; Image; Infection; Investigational Therapies; Knowledge; Lead; Lesion; Lung; Mediating; Modeling; Modification; Multidrug-Resistant Tuberculosis; Necrosis; Necrotic Lesion; Oral; Pathology; Pharmaceutical Preparations; Pharmacology; Prodrugs; Property; Protein Synthesis Inhibition; Protein Synthesis Inhibitors; Pump; Pyrazinamide; Regimen; Relapse; Reporting; Resistance; Ribosomes; Rifampin; Role; Series; Side; Spectinomycin; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Structure; System; Testing; Therapeutic; Toxicology; Tuberculosis; advanced disease; analog; base; caseating granulomas; design; drug candidate; drug development; drug discovery; efflux pump; experimental study; hydrophilicity; improved; in vitro Assay; in vitro activity; in vivo; indexing; insight; lung lesion; macrophage; microbial; mouse model; next generation; novel; side effect; synergism; therapy development; tool; tuberculosis drugs; tuberculosis treatment

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.

抽象的 为了解决耐多药结核病的出现和传播，一种新型的半合成药物 通过细菌选择性核糖体抑制产生了一系列壮观霉素类似物 这些类似物，奇胺酰胺，具有优异的窄谱抗结核活性。 对现有结核病治疗药物产生耐药性，保持针对 MDR- 和 XDR- 的活性 结核病，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，慢性体内小鼠模型的负担。 壮观酰胺的有效抗结核和选择性特性是由于它们能够避免 Rv1258c 泵的内在流出，证明对经典的合成修饰 抗生素可以克服内在外排泵介导的耐药性的挑战。 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 壮观酰胺的体内功效最显着的结果是观察到的协同作用。 在患有结核病的 C3HeB/FeJ 小鼠中，将大观酰胺与利福平和吡嗪酰胺联合使用 在本次更新中，我们的目标是关注与人类中发现的病理学相似的病变。 开发大观酰胺作为能够与以下药物协同作用的组合剂 其他结核病药物通过 3 个迭代目标清除坏死病灶中的感染：(i) 组合 该研究的目的是评估和定义奇酰胺联合治疗。 (ii) 第二代的产生 新一代抗结核大观霉素类似物的设计与合成。 壮观霉素抗结核抗生素的应用，其主要目标是增加治疗效果 通过改善宿主耐受性、生物利用度、分布到体内来实现先导化合物的窗口 (iii) 第二代观酰胺类药物的评价 – 目标 2 中合成的化合物将经历三个迭代测试阶段，包括 微生物评估、药代动力学测试、毒理学和体内功效实验。

项目成果

Comparative pharmacokinetics of spectinamide 1599 after subcutaneous and intrapulmonary aerosol administration in mice.

小鼠皮下和肺内气雾剂给药后 Spectinamide 1599 的药代动力学比较。

• 发表时间: 2019
• 作者: Rathi, Chetan;Lukka, Pradeep B;Wagh, Santosh;Lee, Richard E;Lenaerts, Anne J;Braunstein, Miriam;Hickey, Anthony;Gonzalez;Meibohm, Bernd
• 通讯作者: Meibohm, Bernd

Synthesis, antibacterial action, and ribosome inhibition of deoxyspectinomycins.

脱氧大观霉素的合成、抗菌作用和核糖体抑制。

• 发表时间: 2021-06
• 作者: Dharuman, Suresh;Wilt, Laura A;Liu, Jiuyu;Reeve, Stephanie M;Thompson, Carl W;Elmore, John M;Shcherbakov, Dimitri;Lee, Robin B;Böttger, Erik C;Lee, Richard E
• 通讯作者: Lee, Richard E

Mab2780c, a TetV-like efflux pump, confers high-level spectinomycin resistance in mycobacterium abscessus.

Mab2780c 是一种类似 TetV 的外排泵，可赋予脓肿分枝杆菌高水平的壮观霉素耐药性。

• DOI: 10.1016/j.tube.2022.102295
• 发表时间: 2022-12-01
• 期刊: Tuberculosis
• 影响因子: 3.2
• 作者: Kelley R. Hurst;Gregory A Phelps;L. Wilt;Richard E. Lee;P. Ghosh
• 通讯作者: P. Ghosh

Translational PK/PD of anti-infective therapeutics.

抗感染疗法的转化 PK/PD。

• 发表时间: 2016-09
• 作者: Rathi C;Lee RE;Meibohm B
• 通讯作者: Meibohm B

Development of a Minimalistic Physiologically Based Pharmacokinetic (mPBPK) Model for the Preclinical Development of Spectinamide Antibiotics.

开发基于生理学的简约药代动力学 (mPBPK) 模型，用于 Spectinamide 抗生素的临床前开发。

• 发表时间: 2023-06-17
• 影响因子: 5.4
• 作者: Parmar, Keyur R;Lukka, Pradeep B;Wagh, Santosh;Temrikar, Zaid H;Liu, Jiuyu;Lee, Richard E;Braunstein, Miriam;Hickey, Anthony J;Robertson, Gregory T;Gonzalez;Edginton, Andrea;Meibohm, Bernd
• 通讯作者: Meibohm, Bernd