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

氨基糖苷类抗生素（AGA）是有效的抗生素，其长期以来被用作 强效广谱抗生素，靶点包括革兰氏阴性和革兰氏阴性 病原体和复杂感染性疾病，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， 以及由于阿加和靶修饰机制而产生的抗性。 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，并这样做， 改善毒性。 为了达到这些目的，将筛选所有合成化合物抑制 细菌和真核核糖体，分别指示抗菌活性和毒性， 以及它们对携带特异性抗性的工程细菌菌株的活性 决定因素这些检测的结果将用于反馈回路，以告知设计 和下一个化合物迭代的合成。 将在小鼠中筛选一组选定的优化化合物的耳毒性 耳蜗移植模型，然后在豚鼠耳毒性模型。肾毒性将是 在三个相关的细胞系和先进的化合物在小鼠中测定。抗菌功效 将在小鼠中测定优化的化合物。先进的药代动力学 将在小鼠中测定化合物。 在研究结束时，目标是获得一组经过验证的小型先进化合物 其对野生型和多重耐药革兰氏菌显示出广泛和有效的抗生素活性 阳性和革兰氏阴性细菌，毒性大大降低，适合进一步 发展

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.