细菌核糖体靶向抗生素及耐药机制

Bacterial Ribosome-targeting Antibiotics and Drug-resistance Mechanisms

细菌核糖体是一种主要的抗生素靶标,许多抗生素通过阻断细菌核糖体蛋白合成发挥它们的抗菌作用。核糖体结构的解析为抗生素结合位点提供分子基础。晶体结构数据解释许多生物化学及遗传表型,包括药物的抑制效应,联合用药以增加或减少各自的结合,核糖体组分改变导致细菌耐药。细菌核糖体与天然产生的抗生素及其衍生物复合物晶体结构的解析为抗生素作用机制提供重要基础,且有利于设计有效的抗生素靶向多药物耐受细菌。本文将从结构生物学讨论核糖体靶向抗生素的作用机制以及细菌耐药的分子机制,这将为开发新药物靶向细菌核糖体蛋白合成提供重要线索。

The bacterial ribosome is one of the major antibiotic targets. Many clinical antibiotics target bacterial ribosome and exert their antimicrobial effects by blocking protein synthesis. The deciphering of the crystal structures of bacterial ribosomal particles has provided novel insight into the molecular mechanisms of antibiotic-binding sites. The crystal data also explain biochemical and genetic observations, including how drugs exert their inhibitory effects, how drugs in combination enhance or impede their binding, and how alterations to ribosomal components confer bacterial resistance. Co-crystal structures of naturally antibiotics and their derivatives with ribosomal particles have provided key foundation of their mechanisms of action, and facilitated the design of more effective antibiotics targeting multidrug-resistant bacteria. In this review, we discuss the structural insights into the mechanism of ribosome-targeting antibiotics and the relative bacterial resistance. These will provide unparalleled insight into development of improved antibiotics that suppress bacterial protein synthesis.