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

 说明(申请人提供)：氨基糖苷类抗生素(AGAs)是一种有效的抗生素，长期以来一直被用作有效的广谱抗生素，目标包括革兰氏阴性和革兰氏阴性病原体，以及复杂的感染性疾病，如住院的CAPD和加重的CF。然而，AGAs的显著局限性是AGA导致的永久性听力损失(耳毒性)，据报道影响多达20%的患者群体，肾毒性，以及由于AGA和靶向修饰机制而产生的耐药性。根据广泛的初步结果，将合成并优化两个系列的化合物，即帕罗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，并大大降低毒性。为了达到这些目的，将对所有合成化合物进行筛选，以确定它们抑制细菌和真核核糖体的能力(分别表示抗菌活性和毒性)，以及它们对携带特定抗性决定因素的工程菌的活性。这些分析的结果将被用于反馈循环，为下一代化合物的设计和合成提供信息。选择一组优化的化合物将在小鼠耳蜗外植体模型中筛选耳毒性，然后在豚鼠耳毒性模型中进行筛选。豚鼠模型还将用于评估肾脏毒性和全身毒性。优化后的化合物的抗菌效果将在小鼠身上进行测定。在研究结束时，目标是有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的革兰氏阳性和革兰氏阴性细菌显示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。

 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.