Evaluation of Streptamine Analogs to Overcome Resistance to Apramycin

链霉胺类似物克服安普霉素耐药性的评价

基本信息

批准号：
10557532
负责人：
David Crich
金额：
$ 19.13万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-11-10 至 2024-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10557532
关键词：
Acinetobacter Aminoglycoside Antibiotics Aminoglycoside resistance Aminoglycosides Anti-Bacterial Agents Antibiotics Bacterial Infections Biological Assay Cells Chemistry Clinical Clinical Trials Communicable Diseases Complex Continuous Ambulatory Peritoneal Dialysis Cytoplasm Development Engineering Ensure Enzyme-Linked Immunosorbent Assay Enzymes Epithelial Cells Escherichia coli Europe Evaluation Feedback Genes Goals Gram-Negative Bacteria Hospitalization Human Hybrids Incubated Infection Isoenzymes Kidney LCN2 gene Literature Measures Methods Methyltransferase Microscopic Mitochondria Modification Monitor Multi-Drug Resistance Organism Parents Positioning Attribute Predisposition Protein Biosynthesis Protein Isoforms Protein Synthesis Inhibition Publishing Rattus Reaction Recombinants Resistance Ribosomes Route Series Site Structure Surface Testing Toxic effect Tubular formation aminoglycoside acetyltransferase analog apramycin carbapenem resistance chemical synthesis clinical candidate design experience glycosylation improved in vivo mutant nephrotoxicity novel ototoxicity pathogen resistance mechanism screening therapy development translation assay

Acinetobacter Aminoglycoside Antibiotics Aminoglycoside resistance Aminoglycosides Anti-Bacterial Agents Antibiotics Bacterial Infections Biological Assay Cells Chemistry Clinical Clinical Trials Communicable Diseases Complex Continuous Ambulatory Peritoneal Dialysis Cytoplasm Development Engineering Ensure Enzyme-Linked Immunosorbent Assay Enzymes Epithelial Cells Escherichia coli Europe Evaluation Feedback Genes Goals Gram-Negative Bacteria Hospitalization Human Hybrids Incubated Infection Isoenzymes Kidney LCN2 gene Literature Measures Methods Methyltransferase Microscopic Mitochondria Modification Monitor Multi-Drug Resistance Organism Parents Positioning Attribute Predisposition Protein Biosynthesis Protein Isoforms Protein Synthesis Inhibition Publishing Rattus Reaction Recombinants Resistance Ribosomes Route Series Site Structure Surface Testing Toxic effect Tubular formation aminoglycoside acetyltransferase analog apramycin carbapenem resistance chemical synthesis clinical candidate design experience glycosylation improved in vivo mutant nephrotoxicity novel ototoxicity pathogen resistance mechanism screening therapy development translation assay

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项目摘要

Aminoglycoside antibiotics (AGAs) are potent antibiotics which have long been used as potent broad-spectrum antibiotics, with targets including Gram-negative and Gram-positive pathogens, and complex infectious diseases such as hospitalized CAPD and exacerbated CF. Apramycin is a novel aminoglycoside antibiotic that retains all of the typical advantages of the aminoglycosides but, because of its unusual structure, offers the additional benefits of avoidance of the vast majority of aminoglycoside resistance determinants and of reduced oto- and nephrotoxicity. As such apramycin is currently in clinical trials in Europe and in the USA for the treatment of multidrug-resistant Gram-negative infections. A major advantage of apramycin is its lack of susceptibility to activity-damaging alteration by aminoglycoside modifying enzymes, with the single exception of the aminoacetyltransferase isozyme AAC(3)-IV, which portends well for its use against carbapenem- resistant Gram-negative infections. Nevertheless, resistance due to the acquisition of the AAC(3)-IV gene will eventually inevitably emerge. The goal of this proposal is to test the novel hypothesis that advanced apramycin analogs (apralogs) can be designed and easily prepared that circumvent the AAC(3)-IV resistance determinant through the introduction of a simple hydroxy or alkoxy group at the 2-position on the deoxystreptamine core of apramycin, ie, based on the streptamine core. To test this novel hypothesis a series of some forty advanced apralogs will be prepared based on the streptamine core and screened, in an iterative feedback loop, for antibacterial activity in the presence of AAC(3)-IV and other resistance mechanisms. Compounds will also be screened for activity at the target level using cell-free translation assays with bacterial ribosomes and for selectivity over eukaryotic ribosomes using comparable cell-free translation assays with mutant bacterial ribosomes carrying human decoding A sites. These later studies will provide a measure of selectivity and are predictive of toxicity, thereby ensuring that the excellent toxicity profile of the parent apramycin is retained in the new analogs. At the end of the study, the goal is to have a small set of advanced compounds that are not susceptible to the AAC(3)-IV mechanism of resistance, and retain the otherwise excellent broad spectrum activity and minimal toxicity of the parent apramycin.

氨基糖苷抗生素（AGA）是有效的抗生素，长期以来一直用作有效的广谱抗生素，具有包括革兰氏阴性和革兰氏阳性的靶标病原体和复杂的传染病，例如住院的CAPD和恶化的CF。 Apramycin是一种新型氨基糖苷抗生素，保留所有典型优势在氨基糖苷中，但由于其不寻常的结构，它提供了额外的好处避免绝大多数氨基糖苷耐药性决定因素和降低的oto- 和肾毒性。因此，这种Apramycin目前正在欧洲和美国进行临床试验多药抗革兰氏阴性感染的治疗。 Apramycin的主要优势是它缺乏对活动损害的敏感性通过修饰酶的氨基糖苷改变，单一的除外氨基乙酰转移酶同工酶AAC（3）-IV，它很好地预测了其对抗碳青霉烯 - 抗革兰氏阴性感染。然而，由于获得的抵抗 AAC（3）-IV基因最终将不可避免地出现。该提议的目的是测试小说假设高级Apramycin类似物（Apralogs）可以设计并易于制备通过引入简单的基于Apramycin的脱氧蛋白毒素核心的2位，IE，IE，基于2位的羟基或烷氧基在链霉菌核心上。为了检验这个新的假设基于链霉素核心，并在迭代反馈回路中筛选用于抗菌在AAC（3）-IV和其他电阻机制的存在下的活性。化合物也将是使用细菌的无细胞翻译测定在目标水平上筛选活动水平的活动核糖体和对真核核糖体的选择性，使用可比的无细胞翻译携带人类解码位点的突变细菌核糖体的测定。这些后来的研究将提供选择性的度量并预测毒性，从而确保在新的类似物中保留了母亲Apramycin的出色毒性特征。在研究结束时，目标是拥有一小部分高级化合物不容易受到AAC（3）-IV抗性机制，并保留原本出色的父型阿普霉素的广泛活性和最小的毒性。