Design of novel antibiotics that bind to the ribosomal acyltransfer site
Design of novel antibiotics that bind to the ribosomal acyltransfer site
复制标题
DOI：
10.1021/ja011695m
复制
发表时间：
2002-04-03
影响因子：
15
通讯作者：
Mobashery, S
中科院分区：
文献类型：
--
作者：
Haddad, J;Kotra, LP;Mobashery, S
结合细菌核糖体RNA A位点的新胺结构被用于新型氨基糖苷的设计。该设计考虑了RNA和氨基糖苷之间相互作用的立体和电子贡献，以及从剑桥结构数据库和国家癌症研究所3-D数据库中随机搜索273,000种适合核糖体氨基糖苷结合口袋的化合物。总共设计并随后合成了7种化合物，期望它们能与A位点RNA结合。事实上，所有的合成化合物都被发现与母抗生素奈胺结合靶RNA，解离常数在较低的微摩尔范围内。合成的化合物对一系列重要致病菌的抗菌活性进行了评价。这些设计抗生素对这些病原体，包括对氨基糖苷高表达抗性酶的生物体，显示出显著增强的抗菌活性。此外，对四种含两种重要氨基糖苷抗性酶的合成化合物的分析表明，这些化合物是非常差的底物；因此，正如体内和体外实验所支持的那样，这些合成抗生素的活性似乎不会受到现有耐药机制的影响。本文披露的设计原则有望产生一系列不受现有耐药机制影响的设计抗生素。
The structure of neamine bound to the A site of the bacterial ribosomal RNA was used in the design of novel aminoglycosides. The design took into account stereo and electronic contributions to interactions between RNA and aminoglycosides, as well as a random search of 273 000 compounds from the Cambridge structural database and the National Cancer Institute 3-D database that would fit in the ribosomal aminoglycoside-binding pocket. A total of seven compounds were designed and subsequently synthesized, with the expectation that they would bind to the A-site RNA. Indeed, all synthetic compounds were found to bind to the target RNA comparably to the parent antibiotic neamine, with dissociation constants in the lower micromolar range. The synthetic compounds were evaluated for antibacterial activity against a set of important pathogenic bacteria. These designer antibiotics showed considerably enhanced antibacterial activities against these pathogens, including organisms that hyperexpressed resistance enzymes to aminoglycosides. Furthermore, analyses of four of the synthetic compounds with two important purified resistance enzymes for aminoglycosides indicated that the compounds were very poor substrates; hence the activity of these synthetic antibiotics does not appear to be compromised by the existing resistance mechanisms, as supported by both in vivo and in vitro experiments. The design principles disclosed herein hold the promise of the generation of a large series of designer antibiotics uncompromised by the existing mechanisms of resistance.