Rational Design of Antibiotics Targeted at the Ribosome

快速和广泛出现的耐药病原体产生了对新的抗菌药物的协调一致的方法的迫切需要。 该提案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前沿的合成化学和筛选方法相结合，将用于利用细菌核糖体的新兴结构数据，这是抗生素的一个已证实的靶点。 选定的天然抗生素将作为范例的设计库组成的新的氨基糖苷类衍生物和硫肽模拟物。 核糖体靶位点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设计工作。 化合物文库将使用会聚途径合成。 将通过Anadys Pharmaceuticals针对RNA靶标开发的荧光试验筛选化合物文库对核糖体靶标的活性。基于结构的配体设计的核糖体，最复杂的大分子组件之一，与结构复杂的配体的有效合成和筛选的整合代表了一个艰巨的挑战。 拟议研究的好处将超越直接的抗生素发现工作，为RNA作为合成药物的可行靶点提供原理证明。拟议的商业应用：这项研究旨在发现潜在的抗生素先导化合物，用于治疗细菌感染，特别是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.