Rational Design of Antibiotics Targeted at the Ribosome

描述(由申请人提供)：抗生素耐药病原体的迅速和广泛出现产生了对新的抗感染药物采取协调一致的方法的迫切需要。该提案的长期目标是开发针对抗生素耐药细菌的核糖体RNA(RRNA)的新型有效抗菌药。具体地说，将开发一系列识别核糖体解码位点RNA(A-Site)的领先小分子，通过反复几轮合成和靶标结合、抑制蛋白质合成和细菌生长的测试来选择抗菌候选药物。核糖体A位点是抗生素的主要靶点，我们最近发现的天然氨基糖苷类和一系列新的化学上无关的抗菌药证实了这一点。合理的基于结构的设计加上多维药物优化，使用来自一系列生化和生物检测的测试数据，将使我们能够开发出一种对已知细菌耐药性机制不敏感的新型抗生素。这些新的抗菌A位配体将构成第一类抗生素，它是通过合理的药物发现方法开发出来的，专门针对细菌核糖体的RNA成分。

DESCRIPTION (provided by applicant): Rapid and widespread emergence of antibiotics-resistant pathogens creates an urgent need for concerted approaches towards novel antiinfectives. The long-term objective of this proposal is the development of novel potent antibacterials that target the ribosomal RNA (rRNA) of antibiotics-resistant bacteria. Specifically, a lead series of small molecules that recognize the ribosomal decoding-site RNA (A-site) will be developed to select an antibacterial drug candidate by iterative rounds of synthesis and testing for target binding, inhibition of protein synthesis and bacterial growth. The ribosomal A-site constitutes a prime target for antibiotics, validated by the naturally occurring aminoglycosides and a novel series of chemically unrelated antibacterials that we have discovered recently. Rational structure-based design along with multi-dimensional drug optimization, using testing data from a range of biochemical and biological assays, will allow us to develop a novel class of antibiotics that are not susceptible to known bacterial resistance mechanisms. These novel antibacterial A-site ligands will constitute the first class of antibiotics that has been developed by a rational approach of drug discovery specifically directed at an RNA component of the bacterial ribosome.