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- Title
trans-Translation inhibitors bind to a novel site on the ribosome and clear Neisseria gonorrhoeae in vivo.
- Authors
Aron, Zachary D.; Mehrani, Atousa; Hoffer, Eric D.; Connolly, Kristie L.; Srinivas, Pooja; Torhan, Matthew C.; Alumasa, John N.; Cabrera, Mynthia; Hosangadi, Divya; Barbor, Jay S.; Cardinale, Steven C.; Kwasny, Steven M.; Morin, Lucas R.; Butler, Michelle M.; Opperman, Timothy J.; Bowlin, Terry L.; Jerse, Ann; Stagg, Scott M.; Dunham, Christine M.; Keiler, Kenneth C.
- Abstract
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. Antibiotic-resistant bacterial pathogens pose a substantial threat to human health. Here, aided by structural analyses, the authors describe the molecular mechanism behind the activity of a series of compounds that inhibit trans-translation and are effective in eradicating N. gonorrhoeae infection in mice.
- Subjects
NEISSERIA gonorrhoeae; RIBOSOMES; BINDING sites; GENETIC translation; RIBOSOMAL proteins; PROTEIN conformation; ANTIBIOTICS
- Publication
Nature Communications, 2021, Vol 12, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-021-22012-7