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(申请人提供)：从数值上看，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，这种方法只成功地应用于少数几个选定的支架。重新回顾这一方法，我们将重点放在检查低分子抗生素壮观霉素上，尽管它的药理作用是安全的，但我们认为它被忽视了。壮观霉素是一种氨基环素抗生素，它通过与30S核糖体结合在一个在细菌病原体中高度保守的独特位置来特异性地抑制细菌蛋白质的合成。虽然壮观霉素在无细胞检测中是有效的，但它的临床应用仅限于淋球菌感染的二线治疗。上世纪80年代，开发壮观霉素类似物的尝试导致了新药的发现，这种药物对不同的细菌病原体显示出更好的活性，并进入后期临床试验，然后因商业原因被撤回，验证了修改这一核心以获得更有效的药物世代的可能性。鉴于最近多重耐药细菌的增加，当半合成广谱壮观霉素类似物最后一次被检测时，这些细菌还没有出现，我们重新研究了开发新的壮观霉素类似物作为耐药生物治疗的可能性。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，产生了几个系列的类似物，这些类似物保持了壮观霉素良好的核糖体亲和力，并在30S核糖体螺旋34和核糖体蛋白RpsE环的界面上获得了一个独特的结合口袋。这些化合物具有极好的安全性和远高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芳基取代氨基环菌素。我们最初的一组化合物中最有效的化合物显示：良好的广谱抗菌活性，包括对 NIAID优先生物防御病原体；靶向抑制蛋白质合成；良好的药代动力学特征；以及出色的抗S。肺炎杆菌在体内的活动情况。我们认为，氨基环菌素代表着一种被忽视的化学型的重要重新发现，可用于治疗耐药和生物防御性感染。这一系列的进一步发展将着眼于三个目标：(I)在七个目标亚系列中进一步进行基于结构的设计和合成具有高抗菌效力的新型氨基环菌素；(Ii)确认新出现的先导化合物的作用模式，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来进行先导化合物的开发，其中包括全面的抗菌素评估、体外ADME、药代动力学测试、毒理学和体内疗效实验。在每个阶段之后，这些数据将被用于指导未来几代化合物的设计和合成，并选择最好的化合物进入下一阶段，以便从这项研究中产生适合临床前开发的可行的、特征良好的候选药物。