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: 9082038
• 负责人: David Crich
• 金额: $ 64.27万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-06 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9082038
• 关键词: Affect; Aminoglycoside Antibiotics; Aminoglycosides; Animal Model; Anti-Bacterial Agents; Antibiotic Therapy; Antibiotics; Bacteria; Biological Assay; Cavia; Clinic; 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; Multiple drug resistant Mycobacteria Tuberculosis; Mus; Organism; Paromomycin; Predisposition; Property; Reporting; Resistance; Ribosomes; Series; Shapes; Testing; Toxic effect; Transferase; analog; apramycin; base; clinical application; design; hearing impairment; improved; methicillin resistant Staphylococcus aureus; mutant; nephrotoxicity; next generation; novel; ototoxicity; pathogen; patient population; public health relevance; resistance mechanism; screening; systemic toxicity

 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（由申请人提供）：氨基糖苷类抗生素（AGA）是一种强效抗生素，长期以来一直用作强效广谱抗生素，靶点包括革兰氏阴性和革兰氏阴性病原体，以及复杂感染性疾病，如住院CAPD和加重CF。然而，AGA的显著局限性是阿加诱导的永久性听力丧失（耳毒性），据报告影响高达20%的患者人群、肾毒性和由于阿加和靶点修饰机制引起的耐药性。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，将合成和优化其抑制革兰氏阳性和革兰氏阴性野生型和多药耐药细菌的能力，并这样做的毒性大大降低。为了实现这些目的，将筛选所有合成化合物的抑制细菌和真核核糖体的能力，分别指示抗菌活性和毒性，以及它们对携带特异性抗性决定簇的工程化细菌菌株的活性。这些测定的结果将用于反馈回路，以告知化合物的下一次迭代的设计和合成。将在小鼠耳蜗外植体模型中筛选一组选定的优化化合物的耳毒性，然后在豚鼠耳毒性模型中筛选。还将使用豚鼠模型评价肾毒性和全身毒性。将在小鼠中测定优化化合物的抗菌功效。在研究结束时，目标是获得一组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具有广泛而有效的抗生素活性，毒性大大降低，适合进一步开发。