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

• 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
• 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

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.

氨基糖苷类抗生素（AGA）是有效的抗生素，其长期以来被用作 强效广谱抗生素，靶点包括革兰氏阴性和革兰氏阳性 病原体和复杂感染性疾病，如住院CAPD和加重CF。 安普霉素是一种新型的氨基糖苷类抗生素，保留了所有的典型优点 但由于其不寻常的结构，提供了额外的好处， 避免了绝大多数氨基糖苷类耐药决定簇和减少的耳- 和肾毒性。因此，安普霉素目前在欧洲和美国进行临床试验， 多重耐药革兰氏阴性菌感染的治疗。 安普霉素的一个主要优点是它对活性损伤不敏感 氨基糖苷类修饰酶的改变，除了 氨基乙酰转移酶同工酶AAC（3）-IV，这预示着它对碳青霉烯的使用， 耐药革兰氏阴性菌感染。然而，由于收购的阻力， AAC（3）-IV基因最终必然会出现。这个提案的目的是为了测试这部小说 假设先进的安普霉素类似物（apralogs）可以设计和容易地制备 通过引入一个简单的 在安普霉素的脱氧链霉胺核心上的2-位上的羟基或烷氧基，即，基于 在链霉胺核心上 为了验证这一新的假设，将准备一系列约40个先进的apralogs 基于链霉胺核心，并在迭代反馈回路中筛选， 活性在AAC（3）-IV和其他耐药机制的存在下。化合物也将是 使用细菌的无细胞翻译测定筛选在靶水平的活性 核糖体和选择性超过真核核糖体使用可比的无细胞翻译 使用携带人类解码A位点的突变细菌核糖体进行的测定。这些后来的研究 将提供选择性的量度并预测毒性，从而确保 新类似物保留了母体安普霉素的优良毒性特征。 在研究结束时，目标是有一小部分先进的化合物， 不受AAC（3）-IV耐药机制的影响，并保留了其他优异的 广谱活性和母体安普霉素的最小毒性。