Microbiotix, Inc. One Innovation Dr., Worcester, MA, USA.
Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL, USA.
Nat Commun. 2021 Mar 19;12(1):1799. doi: 10.1038/s41467-021-22012-7.
Bacterial ribosome rescue pathways that remove ribosomes stalled on mRNAs during translation have been proposed as novel antibiotic targets because they are essential in bacteria and are not conserved in humans. We previously reported the discovery of a family of acylaminooxadiazoles that selectively inhibit trans-translation, the main ribosome rescue pathway in bacteria. Here, we report optimization of the pharmacokinetic and antibiotic properties of the acylaminooxadiazoles, producing MBX-4132, which clears multiple-drug resistant Neisseria gonorrhoeae infection in mice after a single oral dose. Single particle cryogenic-EM studies of non-stop ribosomes show that acylaminooxadiazoles bind to a unique site near the peptidyl-transfer center and significantly alter the conformation of ribosomal protein bL27, suggesting a novel mechanism for specific inhibition of trans-translation by these molecules. These results show that trans-translation is a viable therapeutic target and reveal a new conformation within the bacterial ribosome that may be critical for ribosome rescue pathways.
我们之前报道了酰氨基噁二唑家族的发现，它们选择性地抑制转译后核糖体拯救途径中的反式翻译。在这里，我们报告了酰氨基噁二唑的药代动力学和抗生素特性的优化，产生了 MBX-4132，它在单次口服剂量后可清除耐多药淋病奈瑟菌感染的小鼠。非停止核糖体的单颗粒低温电子显微镜研究表明，酰氨基噁二唑结合到靠近肽基转移中心的独特位置，并显著改变核糖体蛋白 bL27 的构象，这表明这些分子特异性抑制反式翻译的新机制。这些结果表明反式翻译是一个可行的治疗靶点，并揭示了细菌核糖体内可能对核糖体拯救途径至关重要的新构象。
