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: 8305156
• 负责人: Richard E. Lee
• 金额: $ 94.52万
• 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 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8305156
• 关键词: Aminoglycosides; Anti-Bacterial Agents; Antibiotics; Antitubercular Agents; Bacillus (bacterium); Bacteria; Bacterial Infections; Bacterial Proteins; Binding; Binding Sites; Biochemical; Biological Assay; Biological Availability; Biological Factors; Capromycin; Cells; Clinical; Clinical Trials; Computer Assisted; Data; Development; Drug Design; Drug Kinetics; Drug resistance; Drug resistance in tuberculosis; Ensure; Evaluation; Future; Future Generations; Generations; Genetic; Infection; Kanamycin; Lead; Linezolid; Mediating; Modification; Molecular; Molecular Weight; Multi-Drug Resistance; Multidrug-Resistant Tuberculosis; Mutagenesis; Mycobacterium tuberculosis; Neisseria gonorrhoeae; Oral; Organism; Penetration; Prodrugs; Protein Biosynthesis; Protein Synthesis Inhibition; Protein Synthesis Inhibitors; Protocols documentation; Pump; Research; Research Proposals; Resistance; Ribosomes; Series; Serum; Site; Spectinomycin; Staging; Streptomycin; Structure; Techniques; Testing; Therapeutic Agents; Tuberculosis; analog; antimicrobial; base; beta-Lactam Resistance; design; drug candidate; drug development; drug discovery; drug resistant bacteria; genome sequencing; improved; in vivo; methicillin resistant Staphylococcus aureus; microbial; mycobacterial; novel; pathogen; research study; safety testing; scaffold; tuberculosis drugs; uptake; Aminoglycosides; Anti-Bacterial Agents; Antibiotics; Antitubercular Agents; Bacillus (bacterium); Bacteria; Bacterial Infections; Bacterial Proteins; Binding; Binding Sites; Biochemical; Biological Assay; Biological Availability; Biological Factors; Capromycin; Cells; Clinical; Clinical Trials; Computer Assisted; Data; Development; Drug Design; Drug Kinetics; Drug resistance; Drug resistance in tuberculosis; Ensure; Evaluation; Future; Future Generations; Generations; Genetic; Infection; Kanamycin; Lead; Linezolid; Mediating; Modification; Molecular; Molecular Weight; Multi-Drug Resistance; Multidrug-Resistant Tuberculosis; Mutagenesis; Mycobacterium tuberculosis; Neisseria gonorrhoeae; Oral; Organism; Penetration; Prodrugs; Protein Biosynthesis; Protein Synthesis Inhibition; Protein Synthesis Inhibitors; Protocols documentation; Pump; Research; Research Proposals; Resistance; Ribosomes; Series; Serum; Site; Spectinomycin; Staging; Streptomycin; Structure; Techniques; Testing; Therapeutic Agents; Tuberculosis; analog; antimicrobial; base; beta-Lactam Resistance; design; drug candidate; drug development; drug discovery; drug resistant bacteria; genome sequencing; improved; in vivo; methicillin resistant Staphylococcus aureus; microbial; mycobacterial; novel; pathogen; research study; safety testing; scaffold; tuberculosis drugs; uptake

DESCRIPTION (provided by applicant): Due to the recent rise in multi-drug resistant organisms, we investigated the potential for developing existing validated natural product scaffolds to produce new semi synthetic antibiotics with more potent activity. We focused on the low molecular weight aminocyclitol spectinomycin as it: has been under studied; has a safe pharmacological profile; targets a ribosomal binding site highly conserved across bacterial pathogens, but separate from other aminoglycosides; is potent in cell free assays; is structurally tractable, allowing for advanced synthetic modification using structure based drug design techniques; has limited clinical use due to bacterial penetration and uptake issues. Several novel analogs were generated and screened against panels of both sensitive and drug resistant bacteria to find compounds with improved anti-bacterial activity. From these series, we discovered a novel class of anti-tuberculosis agents, the spectinamides. The most potent of our compounds demonstrate: excellent anti-tuberculosis activity; on target inhibition of protein synthesis in M. tuberculosis; no cross resistance to existing anti-tuberculosis drugs including those active at the ribosome (Streptomycin, Kanamycin, Capreomycin and Linezolid); good pharmacokinetic profiles including excellent serum and microsomal stability; and anti- tuberculosis activity in vivo. Preliminary results show that improved activity of spectinamides results in part from superior uptake into TB bacilli. We believe the spectinamides are an important discovery of a new chemotype that can be used for the treatment of drug resistant M. tuberculosis infections which we plan to expand and further develop through this collaborative research proposal in three research aims: (i) Compound development - computer aided drug design will be used in an iterative drug development cycle for the design and synthesis of spectinamides with high anti-tubercular potency; (ii) Mode of action - Molecular techniques, including whole genome sequencing, will be used to determine the genetic basis for the improved activity and uptake of the spectinamides against TB; biochemical assays will be used evaluate mode of action of lead compounds at the target level to ensure compounds that progress in our lead development cycle remain potent and selective for inhibition of bacterial protein synthesis; (iii) Lead development and characterization - Compounds synthesized will progress through three stages of tests that include microbial assessment, pharmacokinetic testing, toxicologic and in vivo efficacy experiments. After each stage, the data will be used in further design and synthesis cycles in aim 1 and the best compounds will be selected to move on to the next stage such that viable, well characterized drug candidates will emerge from this study. In this study we propose to develop a novel class of protein synthesis inhibitors to treat problematic multi-drug resistant tuberculosis infections. Compounds discovered in this study may also have the potential to treat other drug resistant bacterial diseases.

描述（由申请人提供）：由于多药耐药生物的最近增加，我们研究了开发现有的经过验证的自然产品支架，以产生具有更有效活性的新的半合成抗生素。我们专注于低分子量氨基细胞质素霉素：已经进行了研究；具有安全的药理特征；靶向在细菌病原体中高度保守的核糖体结合位点，但与其他氨基糖苷分开。在无细胞测定中有效；在结构上是可进行的，可以使用基于结构的药物设计技术进行高级合成修饰；由于细菌渗透和吸收问题，临床使用有限。产生了几种新型类似物，并针对敏感和耐药细菌的面板进行筛选，以找到具有改善抗细菌活性的化合物。从这些系列中，我们发现了一类新型的抗结核剂，即尺寸。我们最有效的化合物表明：出色的抗结核活性；在结核分枝杆菌中靶向蛋白质合成的目标抑制；对现有的抗结核药物没有跨耐药性，包括活跃的核糖体（链霉素，卡纳米霉素，卡牛霉素和linezolid）；良好的药代动力学特征，包括出色的血清和微粒体稳定性；体内抗结核活性。初步结果表明，谱胺的活性改善的部分原因是从上级摄取TB杆菌。我们认为，光谱酰胺是一种新的化学型的重要发现，可用于治疗耐药性结核分枝杆菌感染，我们计划通过这项协作性研究建议在三个研究目的中扩展和进一步发展：（i）复合开发 - 计算机辅助药物设计将用于与高抗Antymidenamidenamide的迭代药物开发周期中，用于高位抗抗原剂， （ii）作用模式 - 包括整个基因组测序在内的分子技术将用于确定改善活性和摄取光谱胺对TB的遗传基础；将使用生化测定法评估铅化合物在靶水平上的作用方式，以确保我们铅发育周期中进展的化合物保持有效和选择性，以抑制细菌蛋白质的合成； （iii）铅发育和表征 - 化合物合成的化合物将通过三个测试阶段进行，包括微生物评估，药代动力学测试，毒理学和体内功效实验。在每个阶段之后，数据将用于进一步的设计和AIM 1中的合成周期，并且将选择最佳化合物进入下一阶段，以便从这项研究中出现可行的，有特征的候选药物。在这项研究中，我们建议开发一种新型的蛋白质合成抑制剂，以治疗有问题的多药结核病感染。在这项研究中发现的化合物也可能有可能治疗其他耐药细菌疾病。