Evaluation of Streptamine Analogs to Overcome Resistance to Apramycin

氨基糖苷类抗生素是一种强效抗生素，长期以来一直被用作 强效广谱抗生素，靶标包括革兰氏阴性和革兰氏阳性 病原体，以及复杂的传染病，如住院的CAPD和加重的CF。 安普霉素是一种新的氨基糖苷类抗生素，它保留了所有典型的优点 氨基糖苷类化合物，但由于其特殊的结构，提供了 避免了绝大多数氨基糖苷类耐药决定因素和降低了听力。 还有肾毒性。因此，安普霉素目前正在欧洲和美国进行临床试验 耐多药革兰氏阴性菌感染的治疗。 安普霉素的一个主要优点是它对活性损伤不敏感。 氨基糖苷类修饰酶的改变，唯一的例外 氨基乙酰转移酶同工酶AAC(3)-IV，这预示着它将很好地用于治疗碳青霉烯- 耐药的革兰氏阴性感染。尽管如此，由于收购 Aac(3)-IV基因最终将不可避免地出现。这项提议的目的是测试这部小说 高级安普霉素类似物(阿帕罗格)可以设计和容易制备的假说 通过引入简单的AAC(3)-IV抗性决定簇 安普霉素脱氧链胺核心上2-位的羟基或烷氧基，即 在链胺核心上。 为了验证这一新的假设，将准备一系列约40个高级apralog 基于链胺核心，并在迭代反馈环中筛选抗菌药物 在AAC(3)-IV和其他抗性机制存在下的活性。化合物也将是 使用细菌的无细胞翻译分析筛选目标水平的活性 核糖体和使用可比的无细胞翻译的真核核糖体的选择性 用携带人类解码A位点的突变细菌核糖体进行检测。这些后来的研究 将提供选择性的度量并可预测毒性，从而确保 在新的类似物中保留了母体安普霉素的良好毒性特征。 在研究结束时，目标是拥有一小部分先进的化合物，这些化合物 不受AAC(3)-IV抗性机制的影响，并保留了其他优良的 母体安普霉素的广谱活性和最小毒性。

Aminoglycoside antibiotics (AGAs) are potent antibiotics which have long been used as potent broad-spectrum antibiotics, with targets including Gram-negative and Gram-positive pathogens, and complex infectious diseases such as hospitalized CAPD and exacerbated CF. Apramycin is a novel aminoglycoside antibiotic that retains all of the typical advantages of the aminoglycosides but, because of its unusual structure, offers the additional benefits of avoidance of the vast majority of aminoglycoside resistance determinants and of reduced oto- and nephrotoxicity. As such apramycin is currently in clinical trials in Europe and in the USA for the treatment of multidrug-resistant Gram-negative infections. A major advantage of apramycin is its lack of susceptibility to activity-damaging alteration by aminoglycoside modifying enzymes, with the single exception of the aminoacetyltransferase isozyme AAC(3)-IV, which portends well for its use against carbapenem- resistant Gram-negative infections. Nevertheless, resistance due to the acquisition of the AAC(3)-IV gene will eventually inevitably emerge. The goal of this proposal is to test the novel hypothesis that advanced apramycin analogs (apralogs) can be designed and easily prepared that circumvent the AAC(3)-IV resistance determinant through the introduction of a simple hydroxy or alkoxy group at the 2-position on the deoxystreptamine core of apramycin, ie, based on the streptamine core. To test this novel hypothesis a series of some forty advanced apralogs will be prepared based on the streptamine core and screened, in an iterative feedback loop, for antibacterial activity in the presence of AAC(3)-IV and other resistance mechanisms. Compounds will also be screened for activity at the target level using cell-free translation assays with bacterial ribosomes and for selectivity over eukaryotic ribosomes using comparable cell-free translation assays with mutant bacterial ribosomes carrying human decoding A sites. These later studies will provide a measure of selectivity and are predictive of toxicity, thereby ensuring that the excellent toxicity profile of the parent apramycin is retained in the new analogs. At the end of the study, the goal is to have a small set of advanced compounds that are not susceptible to the AAC(3)-IV mechanism of resistance, and retain the otherwise excellent broad spectrum activity and minimal toxicity of the parent apramycin.