trans-Translation inhibitors bind to a novel site on the ribosome and clear Neisseria gonorrhoeae in vivo

• DOI: 10.1038/s41467-021-22012-7
• Publication Date: 2021-03-19T13:05:27Z
• Authors: Zachary D. Aron; Atousa Mehrani; Eric D. Hoffer; Kristie L. Connolly; Pooja Srinivas; Matthew C. Torhan; John N. Alumasa; Mynthia Cabrera; Divya Hosangadi; Jay S. Barbor; Steven C. Cardinale; Steven M. Kwasny; Lucas R. Morin; Michelle M. Butler; Timothy J. Opperman; Terry L. Bowlin; Ann Jerse; Scott M. Stagg; Christine M. Dunham; Kenneth C. Keiler
• Keywords: Neisseria gonorrhoeae; Peptidyl transferase

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 not conserved humans. We previously reported the discovery of a family acylaminooxadiazoles selectively inhibit trans-translation, main pathway bacteria. Here, we report optimization pharmacokinetic properties acylaminooxadiazoles, producing MBX-4132, which clears multiple-drug resistant Neisseria gonorrhoeae infection mice after single oral dose. Single particle cryogenic-EM studies non-stop show bind to unique site near peptidyl-transfer center significantly alter conformation ribosomal protein bL27, suggesting mechanism for specific inhibition trans-translation by these molecules. These results is viable therapeutic target reveal new within bacterial may be critical pathways.