Development of Aminospectinomycins for Biodefense

用于生物防御的氨基大观霉素的开发

• 批准号: 9291410
• 负责人: Richard E. Lee
• 金额: $ 69.2万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-04 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9291410
• 关键词: Affinity; Aminoglycosides; Anti-Bacterial Agents; Antibiotics; Bacterial Infections; Bacterial Proteins; Binding; Biochemical; Biological Assay; Cells; Chemicals; Clinical; Clinical Trials; Computer Assisted; Data; Development; Drug Design; Drug Kinetics; Drug resistance; Ensure; Enzymes; Evaluation; Future; Future Generations; Generations; Genetic Transcription; In Vitro; Infection; Lead; Medical; Modification; Molecular Weight; Multi-Drug Resistance; National Institute of Allergy and Infectious Disease; Natural Products; Neisseria gonorrhoeae; Organism; Pharmaceutical Preparations; Pharmacology; Positioning Attribute; Preclinical Testing; Predisposition; Property; Protein Biosynthesis; Protein Inhibition; Protein Synthesis Inhibition; Research Personnel; Resistance; Ribosomal Proteins; Ribosomes; Route; Safety; Series; Serum; Site; Spectinomycin; Streptococcus pneumoniae; Structure; Testing; Toxicology; Work; analog; antimicrobial; antimicrobial drug; bacterial resistance; base; biodefense; chemical stability; commercialization; design; drug candidate; drug development; drug discovery; experience; experimental study; improved; in vitro activity; in vivo; neglect; novel; pathogen; preclinical development; public health relevance; resistance mechanism; safety testing; scaffold

DESCRIPTION (provided by applicant): Numerically, the most successful strategy in antibacterial drug discovery has been the synthetic modification of natural products to produce new semisynthetic antibiotics. However, this approach has only been successfully applied to a few select scaffolds. Revisiting this approach, we have focused on examining the low molecular weight antibiotic spectinomycin, which we felt had been neglected, in spite of its safe pharmacological profile. Spectinomycin is an aminocyclitol antibiotic that specifically inhibits bacterial protein synthesis by binding to 30S ribosome at a unique site that is highly conserved across bacterial pathogens. Although, spectinomycin is potent in cell free assays its clinical use it restricted to second line treatment for Neisseria gonorrhoeae infections. Previous attempts to develop spectinomycin analogs, in the 1980s, led to the discovery of trospectinomycin, which showed improved activity against different bacterial pathogens and progressed into late stage clinical trials before being withdrawn for commercial reasons, validating the potential to modify this core to obtain more potent generations of drug. In view of the recent rise in multi-drug resistant bacteria that were not present when semi-synthetic broad spectrum spectinomycin analogs were last examined, we reinvestigated the potential for developing novel spectinomycin analogs as treatments for drug resistant organisms. In recent work we have found spectinomycin core tractable for advanced synthetic modifications producing several series of analogs that maintain the excellent ribosomal affinity of spectinomycin and access a unique binding pocket at the interface of 30S ribosome Helix 34 and a loop of ribosomal protein RpsE. These compounds have an excellent safety profile and far superior chemical stability to spectinomycin. In these efforts, we have recently discovered a novel series of aryl substituted aminospectinomycins with good antibacterial activities. The most potent of our compounds in our initial set demonstrate: good broad spectrum anti-bacterial activity including activity against NIAID priority biodefense pathogens; on target inhibition of protein synthesis; good pharmacokinetic profiles; and excellent anti-S. pneumoniae activity in vivo. We believe the aminospectinomycins represent an important rediscovery of a neglected chemotype that can be used for the treatment of drug resistant and biodefense infections. The further development of this series will be pursued in three aims to: (i) Perform further structure based design and synthesis of novel aminospectinomycins with high antibacterial potency in seven targeted subseries; (ii) Confirm the mode of action of emerging leads and study the potential for cross resistance and inactivation; (iii) Perform lead development through five stages of detailed tests that include a full antimicrobial assessment, in vitro ADME, pharmacokinetic testing, toxicologic and in vivo efficacy experiments. After each stage, the data will be used to guide the design and synthesis of future generations of compounds and to select the best compounds to move on to the next stage such that viable, well characterized drug candidates will emerge from this study suitable for preclinical development.

描述（由申请人提供）：从数字上看，抗菌药物发现中最成功的策略是对天然产物进行合成修饰以生产新的半合成抗生素。然而，这种方法仅成功应用于少数选定的支架。重新审视这种方法，我们重点研究了低分子量抗生素大观霉素，尽管它具有安全的药理学特征，但我们认为它被忽视了。 Spectinomycin 是一种氨基环醇抗生素，通过在细菌病原体中高度保守的独特位点与 30S 核糖体结合，特异性抑制细菌蛋白质合成。尽管奇霉素在无细胞测定中有效，但其临床用途仅限于淋病奈瑟菌感染的二线治疗。先前在 20 世纪 80 年代开发壮观霉素类似物的尝试导致了曲壮观霉素的发现，它对不同细菌病原体表现出改善的活性，并在因商业原因撤回之前进入后期临床试验，验证了修改该核心以获得更多活性的潜力。药物的有效世代。鉴于最近一次检查半合成广谱壮观霉素类似物时不存在的多重耐药细菌的增加，我们重新研究了开发新型壮观霉素类似物作为耐药微生物治疗方法的潜力。在最近的工作中，我们发现壮观霉素核心易于进行高级合成修饰，产生多个系列的类似物，这些类似物保持了壮观霉素优异的核糖体亲和力，并在 30S 核糖体螺旋 34 和核糖体蛋白 RpsE 环的界面处进入独特的结合口袋。这些化合物具有优异的安全性和远优于壮观霉素的化学稳定性。在这些努力中，我们最近发现了一系列具有良好抗菌活性的新型芳基取代氨基大观霉素。我们最初的化合物中最有效的化合物证明：良好的广谱抗菌活性，包括针对细菌的活性 NIAID优先生物防御病原体；蛋白质合成的靶点抑制；良好的药代动力学特征；和优良的抗S。肺炎球菌体内活性。我们相信氨基大观霉素代表了对被忽视的化学型的重要重新发现，可用于治疗耐药性和生物防御感染。该系列的进一步开发将致力于三个目标：（i）进一步基于结构设计和合成七个目标亚系列中具有高抗菌效力的新型氨基大观霉素； (ii) 确认新出现的先导化合物的作用方式并研究交叉耐药和失活的可能性； (iii) 通过五个阶段的详细测试进行先导药物开发，包括全面的抗菌评估、体外 ADME、药代动力学测试、毒理学和体内功效实验。每个阶段之后，数据将用于指导下一代化合物的设计和合成，并选择最佳化合物进入下一阶段，以便从该研究中产生可行的、特征良好的候选药物，适合临床前开发。