Shaping Next Generation Aminoglycoside Antibiotics for Treatment of Multidrug- Resistant Diseases

打造下一代氨基糖苷类抗生素治疗多重耐药性疾病

基本信息

批准号：
9934590
负责人：
David Crich
金额：
$ 59.74万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9934590
关键词：
Affect Aminoglycoside Antibiotics Aminoglycosides Animal Model Anti-Bacterial Agents Antibiotic Therapy Antibiotics Biological Assay Cavia Clinic Cochlea Communicable Diseases Complex Continuous Ambulatory Peritoneal Dialysis Development Disease Resistance Drug resistance Engineering Enzymes Escherichia coli Evaluation Feedback Genes Goals Gram-Negative Bacteria Guinea In Vitro Knowledge Modeling Molecular Multi-Drug Resistance Multidrug-Resistant Tuberculosis Multiple Bacterial Drug Resistance Mus Organism Paromomycin Predisposition Property Reporting Resistance Ribosomes Series Shapes Testing Toxic effect Transferase analog apramycin bacterial resistance base clinical application design improved methicillin resistant Staphylococcus aureus mutant nephrotoxicity next generation novel ototoxicity pathogen patient population permanent hearing loss public health relevance resistance mechanism screening systemic toxicity

项目摘要

DESCRIPTION (provided by applicant): Aminoglycoside antibiotics (AGAs) are potent antibiotics which have long been used as potent broad spectrum antibiotics, with targets including gram negative and gram‐negative pathogens, and complex infectious diseases such as hospitalized CAPD and exacerbated CF. Significant limitations of the AGAs, however, are AGA‐induced permanent hearing loss (ototoxicity), which is reported to affect up to 20% of the patient population, nephrotoxicity, and resistance due to AGA and target modifying mechanisms. Based on extensive preliminary results two series of compounds, paromomycin and apramycin derivatives, will be synthesized and optimized for their ability to inhibit gram positive and gram negative wild type and multidrug resistant bacteria, and to do so with a much reduced toxicity profile. To achieve these ends all synthetic compounds will screened for their ability to inhibit bacterial and eukaryotic ribosomes, indicative of antibacterial activity and toxcity respectively, and for their activity against engineered bacterial strains carrying specific resistance determinants. The results of these assays will be used in a feedback loop to inform the design and synthesis of the next iteration of compounds. A select set of optimized compounds will be screened for ototoxicity in the mouse cochlear explant model and then in the guinea pig model of ototoxicity. The guinea model will also be used to evaluate nephrotoxicity and systemic toxicity. Antibacterial efficacy of the optimized compounds will be determined in mice. At the end of the study, the goal is to have a small validated set of advanced compounds that display broad and potent antibiotic activity against wild type and multidrug resistant gram positive and gram negative bacteria, with much reduced toxicity, suitable for further development.

描述（申请人提供）：氨基糖苷类抗生素（AGA）是强效抗生素，长期以来被用作强效广谱抗生素，治疗目标包括革兰氏阴性和革兰氏阴性病原体，以及复杂的传染病，例如住院CAPD和重症CF。然而，AGA 的局限性是 AGA 引起的永久性听力损失（耳毒性），据报道影响高达 20% 的患者群体、肾毒性、基于广泛的初步结果，将合成和优化两个系列的化合物，巴龙霉素和安普霉素衍生物，以抑制革兰氏阳性和革兰氏阴性野生型和多重耐药细菌的能力。因此，为了实现这些目的，所有合成化合物都将筛选其抑制细菌和真核核糖体的能力，分别是抗菌活性和毒性的指标。这些测定的结果将用于反馈循环，以指导下一代化合物的设计和合成，以筛选对小鼠的耳毒性。耳蜗外植体模型和豚鼠耳毒性模型也将用于评估优化化合物的肾毒性和全身毒性。研究结束时，目标是获得一小部分经过验证的先进化合物，这些化合物对野生型和多重耐药革兰氏阳性和革兰氏阴性细菌表现出广泛而有效的抗生素活性，毒性大大降低，适合进一步开发。

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（2）

N6', N6''', and O4' Modifications to Neomycin Affect Ribosomal Selectivity without Compromising Antibacterial Activity.

新霉素的 N6、N6 和 O4 修饰会影响核糖体选择性，但不会影响抗菌活性。

DOI：
发表时间：
2017-05-12
期刊：
影响因子：
5.3
作者：
Sati, Girish C;Shcherbakov, Dimitri;Hobbie, Sven N;Vasella, Andrea;Böttger, Erik C;Crich, David
通讯作者：
Crich, David

Synthesis of Gentamicin Minor Components: Gentamicin B1 and Gentamicin X2.

庆大霉素次要成分的合成：庆大霉素B1和庆大霉素X2。

DOI：
发表时间：
2020
期刊：
影响因子：
5.2
作者：
Rajasekaran, Parasuraman;Crich, David
通讯作者：
Crich, David

Synthesis and Antibacterial Activity of Propylamycin Derivatives Functionalized at the 5''- and Other Positions with a View to Overcoming Resistance Due to Aminoglycoside Modifying Enzymes.

5-和其他位置功能化的丙霉素衍生物的合成和抗菌活性，以克服氨基糖苷修饰酶引起的耐药性。

DOI：
发表时间：
2021
期刊：
影响因子：
5.3
作者：
Lubriks, Dimitrijs;Zogota, Rimants;Sarpe, Vikram A;Matsushita, Takahiko;Sati, Girish C;Haldimann, Klara;Gysin, Marina;Böttger, Erik C;Vasella, Andrea;Suna, Edgars;Hobbie, Sven N;Crich, David
通讯作者：
Crich, David

Stereospecific synthesis of methyl 2-amino-2-deoxy-(6S)-deuterio-α,β-d-glucopyranoside and methyl 2,6-diamino-2,6-dideoxy-(6R)-deuterio-α,β-d-glucopyranoside: Side chain conformations of the 2-amino-2-deoxy and 2,6-diamino-2,6-dideoxyglucopyranosides.

甲基 2-氨基-2-脱氧-(6S)-氘代-α,β-d-吡喃葡萄糖苷和甲基 2,6-二氨基-2,6-二脱氧-(6R)-氘代-α,β 的立体定向合成

DOI：
发表时间：
2017-08-07
期刊：
影响因子：
3.1
作者：
Kato, Takayuki;Vasella, Andrea;Crich, David
通讯作者：
Crich, David

Structure-Based Design and Synthesis of Apramycin-Paromomycin Analogues: Importance of the Configuration at the 6'-Position and Differences between the 6'-Amino and Hydroxy Series.

安普霉素-巴龙霉素类似物的基于结构的设计和合成：6-位置构型的重要性以及 6-氨基和羟基系列之间的差异。

DOI：
发表时间：
2017-10-18
期刊：
影响因子：
15
作者：
Mandhapati, Appi Reddy;Yang, Guanyu;Kato, Takayuki;Shcherbakov, Dimitri;Hobbie, Sven N;Vasella, Andrea;Böttger, Erik C;Crich, David
通讯作者：
Crich, David