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

• 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
• 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

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.

氨基糖苷抗生素（AGA）是潜在的抗生素，长期以来一直用作 有效的广谱抗生素，其靶标在包括革兰氏阴性和革兰氏阴性含量 病原体和复杂的传染病，例如住院的CAPD和恶化的CF。 但是，AGA的重大局限性是AGA引起的永久性听力损失 （耳毒性），据报道会影响多达20％的患者人群，肾毒性， 以及由于AGA和目标修饰机制引起的电阻。 基于广泛的初步结果 Apramycin衍生物将因其抑制革兰氏阳性的能力而合成并优化 和革兰氏阴性野生型和多药耐药细菌，并以很多 改善毒性特征。 为了实现这些目的，所有合成化合物都将筛选其抑制能力 细菌和真核核糖体分别指示抗菌活性和毒性 以及它们针对具有特定抗性的工程细菌菌株的活动 决定级。这些测定的结果将在反馈循环中使用，以告知设计 并合成化合物的下一个迭代。 将筛选一组精选的优化化合物，以使鼠标中的耳毒性 耳蜗外植体模型，然后在耳毒性的豚鼠模型中。肾毒性将是 在三种相关的细胞系中分析小鼠中的高级化合物。抗菌效率 在小鼠中将确定优化化合物的中化合物。高级药代动力学 化合物将在小鼠中确定。 在研究结束时，目标是拥有一组经过验证的高级化合物集 它表现出针对野生型和耐多药的较广泛而潜在的抗生素活性 阳性和革兰氏阴性细菌，毒性降低，适合进一步 发展。