基于结构设计、合成和评价耐酶氨基糖苷类抗生素

Antibiotic resistance is a serious challenge to the medical community around the world. As a kind of widely used antibiotics, aminoglycosides are also facing the problem of resistance caused by modifying enzymes. To tackle this problem, structural modification on these drugs is extensively investigated. However, most previous effort aimed at enzymes-resistant products failed to attain the goal because of neglecting the innate binding specificity of aminoglycoside-target and chemical characterization of aminoglycosides. To overcome this difficulty, based on the aminoglycoside-target and aminoglycoside-modifying enzyme structural information, we deduced that C6’ and 2'- hydroxyl (or amino) of aminoglycoside are feasible sites for modification for enzymes-resistant analogs. To verify these hypotheses, our group will rationally design and synthesize a series of modified products, evaluate the activity and mechanism thereof. Finally we are trying to find out some novel modifying sites and useful chemical entities with high activity and modifying-enzyme resistance. Previously we had gain some positive result with the similar idea of this proposal, so we anticipate to find a new way for the rational modification of these antibiotics.

抗生素耐药是当今世界医学界的一个严峻挑战，作为临床上广为使用的抗生素，氨基糖苷同样也面临耐药问题，主因是细菌表达氨基糖苷修饰酶。为解决这个问题，人们对氨基糖苷的结构做了不少改造研究，但结果多因忽视氨基糖苷-靶点作用的内在特殊性以及氨基糖苷分子本身特点而不理想。在此，本申请课题基于氨基糖苷-靶点和氨基糖苷-修饰酶的结构信息，通过比较分析，推断出氨基糖苷新霉胺环I上C6’及2’-OH(NH2)是两个全新的通用修饰改造位点。基于这个设想本课题组理性设计了一系列相应修饰产物，并拟通过合成、活性评价和机理分析来对此设想进行验证，期望能寻找到全新的通用修饰改造位点和有用的耐修饰酶、高活性的化学实体。本课题设计思想前期有成功的工作基础，有望为此类抗生素的修饰改造探索出一条新的路径。

抗生素耐药是当今世界医学界的一个严峻挑战，作为临床上广为使用的抗生素，氨基糖苷同样也面临耐药问题，主因是细菌表达氨基糖苷修饰酶。为解决这个问题，人们对氨基糖苷的结构做了不少改造研究，但结果多因忽视氨基糖苷-靶点作用的内在特殊性以及氨基糖苷分子本身特点而不理想。在此，本课题基于氨基糖苷-靶点和氨基糖苷-修饰酶的结构信息，通过比较分析，推断出氨基糖苷新霉胺环上的C5及2’-OH(NH2)是两个全新的通用修饰改造位点。基于这个设想本课题组设计了一系列新霉胺C-5位构型翻转的修饰产物，以及一系列卡那霉素A 2’-OH修饰产物，并通过合成、活性评价和作用机理分析来对此设想进行验证。活性评价结果表明新合成的化合物展现了较好的抗菌活性，并有部分分子活性堪比天然产物，有些分子展现了较好的耐药菌杀菌能力。本课题取得结果对氨基糖苷构效关系有进一步拓展，将有助于这类抗生素的开发和应用。