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.

多重耐药革兰氏阴性细菌病原体正在形成新的威胁，具体来说， 耐碳青霉烯类肠杆菌、鲍曼不动杆菌和铜绿假单胞菌（例如， ESKAPE 病原体）。由此产生的感染通常无法治疗或只能用有毒物质治疗 抗菌剂。更令人不安的是，这些感染的发生率正在不断增加 频率。因此，疾病预防控制中心现在将此类生物体归类为抗生素耐药性的首要威胁 等级。迫切需要新的抗感染策略。这个多PI R01应用提出了一种从头开始的方法 药物化学设计和从头碳水化合物合成方法，当与 功能表征和冷冻电镜支持的结构引导设计应该会导致快速发现 新型氨基糖苷类（AG）抗菌剂对耐药革兰氏阴性病原体具有活性。 长期预期成果是 1) 建立新的系统合成方法 基于药物化学 SAR 的氨基糖苷类化学空间探索以及 2) 的发现 新的氨基糖苷结构基序，具有改进的抗耐药细菌活性（例如，AME、RMT- 介导的抵抗）。指导我们方法的基本假设是这样的假设： 由于传统方法的合成限制，许多碳水化合物结构仍未被发现 碳水化合物和半合成方法。相比之下，我们的完全从头合成方法使得 以立体化学选择性方式安装更广泛的碳水化合物。的例子 将探索的结构变异是含有稀有氨基糖、直链糖和 2- 的氨基糖苷类。 脱氧链霉胺 (2-DOS) 替代物旨在规避已知的氨基糖苷类耐药性 机制。