The structure of ribosome-lankacidin complex reveals ribosomal sites for synergistic antibiotics
The structure of ribosome-lankacidin complex reveals ribosomal sites for synergistic antibiotics
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DOI：
10.1073/pnas.0914100107
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发表时间：
2010-02-02
影响因子：
11.1
通讯作者：
Yonath, Ada
中科院分区：
文献类型：
--
作者：
Auerbach, Tamar;Mermershtain, Inbal;Yonath, Ada
结晶学分析表明，罗氏链霉菌产生的17元聚酮类抗生素lankacidin结合在真菌性核糖体大亚基的肽基转移酶中心。生化和功能研究证实了这一发现，并表明干扰肽键的形成。化学探测表明，同一物种产生的第二种抗生素大环内酯lankamycin在邻近的核糖体出口通道上结合。这两种抗生素可同时与核糖体结合，协同抑制细菌生长。lankacidin和lankamycin的结合位点与另一对增效抗生素链状gramins的结合位点部分重叠。因此，至少有两对结构不同的化合物在进化过程中被选择，通过靶向核糖体中的邻近位点来协同作用。这些结果强调了相应的核糖体位点对临床相关增效抗生素开发的重要性，并证明了结构分析在为药物发现提供新方向方面的实用性。
Crystallographic analysis revealed that the 17-member polyketide antibiotic lankacidin produced by Streptomyces rochei binds at the peptidyl transferase center of the eubacterial large ribosomal subunit. Biochemical and functional studies verified this finding and showed interference with peptide bond formation. Chemical probing indicated that the macrolide lankamycin, a second antibiotic produced by the same species, binds at a neighboring site, at the ribosome exit tunnel. These two antibiotics can bind to the ribosome simultaneously and display synergy in inhibiting bacterial growth. The binding site of lankacidin and lankamycin partially overlap with the binding site of another pair of synergistic antibiotics, the streptogramins. Thus, at least two pairs of structurally dissimilar compounds have been selected in the course of evolution to act synergistically by targeting neighboring sites in the ribosome. These results underscore the importance of the corresponding ribosomal sites for development of clinically relevant synergistic antibiotics and demonstrate the utility of structural analysis for providing new directions for drug discovery.