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：
10585038
负责人：
David Crich
金额：
$ 65.47万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-23 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10585038
关键词：
Affect Aminoglycoside Antibiotics Aminoglycosides Animal Model Anti-Bacterial Agents Antibiotic Therapy Antibiotics Biological Biological Assay Cell Line Clinic Cochlea Communicable Diseases Complex Continuous Ambulatory Peritoneal Dialysis Derivation procedure Development Didelphidae Disease Resistance Drug Kinetics Drug resistance ESKAPE pathogens Engineering Enzymes Feedback Genes Goals Gram-Negative Bacteria Hospitalization Human In Vitro Investigation Knowledge Methyltransferase Modeling Modification Molecular Multi-Drug Resistance Multidrug-Resistant Tuberculosis Multiple Bacterial Drug Resistance Mus Organism Parents Paromomycin Positioning Attribute Predisposition Property Protein Isoforms Pseudomonas aeruginosa Rattus Reporting Resistance Ribosomes Series Shapes Skeleton Time Toxic effect Toxicology Transferase analog apramycin bacterial resistance clinical application cytotoxicity design guinea pig model improved in vivo in vivo evaluation kidney cell methicillin resistant Staphylococcus aureus nephrotoxicity next generation novel ototoxicity pathogen patient population permanent hearing loss resistance mechanism single molecule whole genome

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‐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 improved 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 toxicity 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. Nephrotoxicity will be assayed in three relevant cell lines and for advanced compounds in mice. Antibacterial efficacy of the optimized compounds will be determined in mice. Pharmacokinetics of advanced compounds will 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.

氨基糖苷类抗生素（AGAs）是一种强效抗生素，长期以来被用作强效广谱抗生素，目标包括革兰氏阴性菌和革兰氏阴性菌病原体，以及复杂的传染病，例如住院 CAPD 和加重 CF。然而，AGA 的显着局限性是 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，以及由于 AGA 和目标修改机制而产生的阻力。基于广泛的初步结果，两个系列的化合物，巴龙霉素和安普霉素衍生物将被合成并优化其抑制革兰氏阳性菌的能力和革兰氏阴性野生型和多重耐药细菌，并且要这样做改善毒性特征。为了实现这些目标，将筛选所有合成化合物的抑制能力细菌和真核核糖体，分别是抗菌活性和毒性的指标，以及它们对具有特定抗性的工程细菌菌株的活性这些测定的结果将用于反馈循环，为设计提供信息。以及下一次迭代化合物的合成。将筛选一组选定的优化化合物的小鼠耳毒性耳蜗外植体模型和豚鼠模型中都会出现耳毒性。在三种相关细胞系中进行了检测，并在小鼠中检测了高级化合物的抗菌功效。优化后的化合物将在小鼠中进行药代动力学测定。化合物将在小鼠中进行测定。研究结束时，目标是获得一小部分经过验证的先进化合物对野生型和多重耐药革兰氏菌表现出广泛而有效的抗生素活性阳性和革兰氏阴性菌，毒性大大降低，适合进一步发展。