De Novo Synthesis, and Functional and Structural Characterization of Novel Aminoglycoside Analogues to Bypass Resistance Mechanisms and Optimize Selectivity

新型氨基糖苷类似物的从头合成、功能和结构表征，以绕过耐药机制并优化选择性

• 批准号: 10447128
• 负责人: JAMES E KIRBY
• 金额: $ 76.53万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-20 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10447128
• 关键词: Acinetobacter baumannii; Acylation; Address; Amines; Amino Sugars; Aminoglycoside Antibiotics; Aminoglycoside resistance; Aminoglycosides; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotic Resistance; Antibiotics; Bypass; Carbohydrate Chemistry; Carbohydrates; Centers for Disease Control and Prevention (U.S.); Charge; Chemicals; Coupled; Cryoelectron Microscopy; Diamines; ESKAPE pathogens; Enzymes; Event; Frequencies; Goals; Hydrogen Bonding; Hydroxyl Radical; Incidence; Infection; Laboratories; Lead; Mediating; Metabolism; Methodology; Methylation; Methyltransferase; Microbiology; Modification; Multi-Drug Resistance; Organism; Outcome; Parents; Pharmaceutical Chemistry; Positioning Attribute; Pseudomonas aeruginosa; Pyrimidine; Pyrimidines; Resistance; Ribosomes; Route; Scheme; Site; Site-Directed Mutagenesis; Structure; Structure-Activity Relationship; Therapeutic; Variant; analog; antimicrobial; bacterial resistance; bactericide; base; carbapenem-resistant Enterobacteriaceae; carbohydrate structure; clinically relevant; design; emerging antimicrobial resistance; expectation; improved; multi-drug resistant pathogen; nephrotoxicity; novel; ototoxicity; pathogen; pathogenic bacteria; polyol; preservation; protonation; pyridine; resistance mechanism; stereochemistry; structural biology; sugar; targeted treatment; tv watching

There is an emerging threat from multidrug-resistant Gram-negative bacterial pathogens, specifically, carbapenem-resistant Enterobacteriaceae, Acinetobacter baumannii, and Pseudomonas aeruginosa (e.g., ESKAPE pathogens). The resulting infections are often untreatable or treatable only with toxic antimicrobials. More troubling is the fact that the incidences of these infections are occurring with increasing frequency. Therefore, the CDC now categorizes such organisms in their top antibiotic resistance threat level. New anti-infective strategies are urgently needed. This multi-PI R01 application proposes a de novo medicinal chemistry design and de novo carbohydrate synthesis approach, which when coupled with functional characterization and cryo-EM enabled structure-guided design should lead to the rapid discovery of novel aminoglycoside (AG) antimicrobials with activity against resistant Gram-negative pathogens. The long-term expected outcomes are 1) the establishment of new synthetic methodology for systematic medicinal chemistry SAR-based exploration of the aminoglycoside chemical space and 2) the discovery of new aminoglycoside structural motifs with improved activity against resistant bacteria (e.g., AME, RMT- mediated resistance). The underlying hypothesis that guides our approach is the assumption that there are many carbohydrate structures that remain undiscovered due to the synthetic limitations of traditional carbohydrate and semi-synthetic approaches. In contrast, our total de novo synthetic approach enables the installation of a much broader range of carbohydrates in a stereochemically selective manner. Examples of structural variations that will be explored are aminoglycosides with rare aminosugar, linear sugar, and 2- deoxystreptamine (2-DOS) substitutions that are designed to evade known aminoglycoside resistance mechanisms.

抗多药的革兰氏阴性细菌病原体有一个新兴的威胁，特别是 抗碳青霉烯乙酰肝杆菌科，baumannii和铜绿假单胞菌（例如， Eskape病原体）。最终的感染通常不可治疗或仅与有毒 抗菌剂。更令人不安的是，这些感染的发生率随着增加而增加 频率。因此，CDC现在将这种生物分类为其顶部抗生素耐药性威胁 等级。迫切需要新的反感染策略。此多PI R01应用程序提出了从头提出的 药物化学设计和从头碳水化合物合成方法，与 功能表征和启用冷冻EM的结构引导的设计应导致快速发现 新型氨基糖苷（Ag）抗菌抗菌药物具有抗抗性革兰氏阴性病原体的活性。 长期预期的结果是1）建立用于系统的新合成方法论 药物化学基于SAR的氨基糖苷化学空间的探索和2）发现 具有改善抗性细菌活性的新型氨基糖苷结构基序（例如，AME，RMT- 介导的电阻）。指导我们方法的基本假设是存在 由于传统的综合限制，许多碳水化合物结构仍未发现 碳水化合物和半合成方法。相比之下，我们从头综合方法可以实现 以立体化学选择性的方式安装更广泛的碳水化合物。示例的例子 将要探索的结构变化是氨基糖苷，氨基糖，线性糖和2-- 脱氧抑制胺（2-DOS）替代，旨在逃避已知的氨基糖苷耐药性 机制。