Rational Design of Antibiotics Targeted at the Ribosome

抗生素耐药病原体的迅速和广泛出现迫切需要采取协调一致的方法来开发新的抗菌药。这项提议的长期目标是开发克服已知耐药机制的合成抗生素。基于结构的分子设计与尖端的合成化学和筛选方法相结合，将被用来利用细菌核糖体的新结构数据，细菌核糖体已被证明是抗生素的靶标。选定的天然抗生素将作为设计由新的氨基糖苷衍生物和硫肽模拟物组成的文库的范例。核糖体靶位的晶体结构和配体对其分子识别的计算分析将有助于化合物的设计工作。化合物文库将使用聚合路线进行合成。筛选化合物文库对核糖体靶标的活性将通过Anadys制药公司为RNA靶标开发的荧光分析进行。核糖体是最复杂的大分子组装之一，如何将基于结构的配体设计与高效合成结构复杂的配体及其筛选相结合，是一个巨大的挑战。这项拟议研究的好处将超越直接发现抗生素的努力，因为它为RNA作为合成药物的可行靶标提供了原理证明。拟议的商业应用：拟议的研究旨在发现先导化合物，这些化合物是治疗细菌感染的潜在抗生素，特别是对对现有抗生素具有耐药性的病原体。

Rapid and widespread emergence of antibiotic-resistant pathogens creates an urgent need for concerted approaches towards novel antibacterials. The long-term objective of this proposal is the development of synthetic antibiotics that overcome known resistance mechanisms. Structure-based molecular design in combination with leading-edge synthetic chemistry and screening methods will be used to exploit emerging structural data on the bacterial ribosome, a proven target for antibiotics. Selected natural antibiotics will serve as paradigms for the design of libraries consisting of novel aminoglycoside derivatives and thiopeptide mimetics. Crystal structures of the ribosomal target sites and computational analysis of their molecular recognition by ligands will aid the compound design effort. Compound libraries will be synthesized using convergent routes. Screening of compound libraries for their activity on the ribosomal target will be performed by fluorescence assays that have been developed for RNA targets at Anadys Pharmaceuticals. The integration of structure-based ligand design for the ribosome, one of the most complex macromolecular assemblies, with efficient synthesis of structurally complex ligands and their screening represents a formidable challenge. The benefit of the proposed research will extend beyond the immediate antibiotic discovery effort by providing the proof of principle for RNA as a feasible target for synthetic drugs. PROPOSED COMMERCIAL APPLICATIONS: The proposed research is aimed at discovering lead compounds that are potential antibiotics for the therapy of bacterial infections, especially for pathogens with resistance against existing antibiotics.