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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

基本信息

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
项目类别：
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

项目摘要

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.

摘要为了解决耐多药结核病的出现和传播，利用细菌选择性核糖体抑制产生了一系列壮观霉素类似物，出色的窄谱抗结核活性这些类似物，壮观的酰胺，缺乏交叉- 对现有结核病疗法产生耐药性，保持抗MDR和XDR的活性保留大观霉素的高选择性指数，协同减少肺细菌当与其他TB疗法联合使用时，的壮观酰胺的有效抗结核和选择性特性是它们能够避免通过Rv 1258 c泵的内在外排，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。详细SAR 已被开发用于蛋白质合成抑制和外排避免、药代动力学，壮观酰胺的体内功效。最显著的结果是观察到的协同作用，壮观的酰胺与利福平和吡嗪酰胺在携带结核杆菌的C3 HeB/FeJ小鼠中联合使用。病理学与人类相似的病变。在这次更新中，我们的目标是专注于开发壮观酰胺作为能够与之协同作用的组合剂通过3个反复的目标，用其他TB药剂清除坏死病灶中的感染：问题研究本研究的目的是评价和确定壮观酰胺联合治疗，特异性靶向坏死性肉芽肿中的协同活性。(ii)生成第二产生抗结核壮观霉素类似物。下一代的设计和合成大观霉素抗结核抗生素的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、分布到肉芽肿和外排避免。(iii)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，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

期刊论文数量（24）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Aminomethyl spectinomycins as therapeutics for drug-resistant respiratory tract and sexually transmitted bacterial infections.

DOI：
10.1126/scitranslmed.3010572
发表时间：
2015-05-20
期刊：
Science translational medicine
影响因子：
17.1
作者：
Bruhn DF;Waidyarachchi SL;Madhura DB;Shcherbakov D;Zheng Z;Liu J;Abdelrahman YM;Singh AP;Duscha S;Rathi C;Lee RB;Belland RJ;Meibohm B;Rosch JW;Böttger EC;Lee RE
通讯作者：
Lee RE

In vitro pharmacokinetic/pharmacodynamic models in anti-infective drug development: focus on TB.