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

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.

氨基糖苷类抗生素（AGAs）是一种强效抗生素，长期以来被用作有效的广谱抗生素，目标包括革兰氏阴性和革兰氏阳性病原体，以及复杂的传染病，例如住院 CAPD 和加重 CF。安普霉素是一种新型氨基糖苷类抗生素，保留了所有典型优点氨基糖苷类药物，但由于其不寻常的结构，提供了额外的好处避免绝大多数氨基糖苷类耐药决定因素和减少的耳- 和肾毒性。因此，安普霉素目前正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不易受到活性损害的影响氨基糖苷修饰酶的改变，唯一的例外是氨基乙酰转移酶同工酶 AAC(3)-IV，这预示着其可用于对抗碳青霉烯类药物耐药革兰氏阴性菌感染。然而，由于收购 AAC(3)-IV基因最终将不可避免地出现。该提案的目的是测试小说假设可以设计并轻松制备先进的安普霉素类似物（apralogs）通过引入一个简单的方法来规避 AAC(3)-IV 电阻决定因素安普霉素脱氧链霉胺核心2位上的羟基或烷氧基，即基于在链霉胺核心上。为了测试这一新颖的假设，将准备一系列约四十个先进的 apralog 基于链霉胺核心并在迭代反馈循环中筛选抗菌 AAC(3)-IV 和其他耐药机制存在时的活性。化合物也将使用细菌的无细胞翻译测定筛选目标水平的活性核糖体，并使用可比较的无细胞翻译对真核核糖体进行选择性使用携带人类解码 A 位点的突变细菌核糖体进行测定。这些后来的研究将提供选择性测量并预测毒性，从而确保新类似物保留了母体安普霉素的优异毒性特征。研究结束时，目标是获得一小组先进的化合物不易受到 AAC(3)-IV 耐药机制的影响，并保留其他方面优异的特性母体安普霉素的广谱活性和最小毒性。