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: 8495235
• 负责人: Richard E. Lee
• 金额: $ 93.65万
• 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/8495235
• 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

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）：由于最近多重耐药生物体的增加，我们研究了开发现有经验证的天然产物支架以生产具有更有效活性的新半合成抗生素的潜力。我们专注于低分子量的氨基环醇壮观霉素，因为它：已被研究;具有安全的药理学特征;靶向在细菌病原体中高度保守的核糖体结合位点，但与其他氨基糖苷类分开;在无细胞测定中是有效的;结构上易于处理，允许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，其临床应用有限。产生了几种新的类似物，并针对敏感和耐药细菌的小组进行筛选，以找到具有改善的抗菌活性的化合物。从这些系列中，我们发现了一类新的抗结核药物，壮观的酰胺。我们的化合物中最有效的化合物表现出：优异的抗结核活性;靶向抑制M.肺结核;对现有的抗结核药物没有交叉耐药性，包括那些在核糖体上有活性的药物（链霉素、卡那霉素、卷曲霉素和利奈唑胺）;良好的药代动力学特征，包括优异的血清和微粒体稳定性;以及体内抗结核活性。初步结果表明，壮观酰胺活性的提高部分是由于TB杆菌对壮观酰胺的上级吸收。我们相信壮观酰胺是一个重要的发现，一个新的化学型，可用于治疗耐药M。我们计划透过这项合作研究建议，在三个研究目的中扩大及进一步发展结核病感染的研究：（i）化合物开发-电脑辅助药物设计将用于重复药物开发周期，以设计及合成具有高度抗结核效力的壮观酰胺;（ii）作用模式----分子技术，包括全基因组测序，将用于确定提高壮观酰胺抗结核活性和吸收的遗传基础;将使用生物化学试验评估先导化合物在目标水平的作用模式，以确保在我们的先导开发周期中进展的化合物仍然有效并选择性抑制细菌蛋白质合成;（三）先导化合物的开发和表征-合成的化合物将通过三个阶段的测试，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，数据将用于目标1中的进一步设计和合成循环，并将选择最佳化合物进入下一阶段，以便从本研究中产生可行的，充分表征的候选药物。在这项研究中，我们建议开发一类新的蛋白质合成抑制剂来治疗有问题的耐多药结核病感染。在这项研究中发现的化合物也可能具有治疗其他耐药细菌疾病的潜力。