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

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:
10242923
负责人:
JAMES E KIRBY
金额:
$77.26万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-08-20 至 2024-07-31

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中文摘要
翻译
有一个新的威胁来自多重耐药的革兰氏阴性细菌病原体,具体地说, 耐碳青霉烯类肠杆菌科细菌、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是无法治疗的,或者只能用有毒的药物治疗。 抗菌剂。更令人不安的是,这些感染的发病率正在随着越来越多的人 频率因此,美国疾病控制与预防中心现在将这些微生物归类为抗生素耐药性最大的威胁 水平。迫切需要新的抗感染策略。这款多PI R01应用程序提供了一种全新的方式 药物化学设计和从头合成碳水化合物的方法,当与 功能表征和低温EM结构导向设计应该会导致快速发现 具有抗革兰氏阴性病原体活性的新型氨基糖苷类(AG)抗菌剂。 长期的预期结果是:1)建立新的系统综合方法论 药物化学合成孔径雷达对氨基糖苷类化学空间的探索及2)新发现 新的氨基糖苷类结构基序具有更好的抗耐药细菌活性(例如,AME,RMT- 中介抗性)。指导我们方法的基本假设是假设存在 许多碳水化合物结构由于传统的合成限制而仍未被发现 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 以立体化学选择性的方式安装范围更广的碳水化合物。举例 将探索的结构变异是含有稀有氨基糖、直链糖和2-氨基糖的氨基糖苷类化合物。 旨在逃避已知氨基糖苷耐药性的脱氧链胺(2-DOS)替代 机械装置。
英文摘要
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.
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De Novo Synthesis, and Functional and Structural Characterization of Novel Aminoglycoside Analogues to Bypass Resistance Mechanisms and Optimize Selectivity
Use of De Novo Synthesis Approaches and Structure-guided Design to Optimize Therapeutic Properties of Streptothricin Class Antimicrobials
De Novo Synthesis, and Functional and Structural Characterization of Novel Aminoglycoside Analogues to Bypass Resistance Mechanisms and Optimize Selectivity
Use of De Novo Synthesis Approaches and Structure-guided Design to Optimize Therapeutic Properties of Streptothricin Class Antimicrobials
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