Year: 2020
Type: preprint
Abstract: The trans -translation pathway for rescuing stalled ribosomes is conserved and essential in bacterial pathogens but has no mammalian homolog, making it an ideal target for new antibiotics. We previously reported the discovery of a family of acylaminooxadiazoles that selectively inhibit trans -translation, resulting in broad-spectrum antibiotic activity. Optimization of the pharmacokinetic and antibiotic properties of the acylaminooxadiazoles produced MBX-4132, which cleared multiple-drug resistant Neisseria gonorrhoeae infection in mice after a single oral dose. Cryo-EM studies of non-stop ribosomes showed that acylaminooxadiazoles bind to a unique site near the peptidyl-transfer center and significantly alter the conformation of ribosomal protein L27, suggesting a novel mechanism for specific inhibition of trans -translation by these molecules. One Sentence Summary Ribosome rescue inhibitors reveal a new conformation of the ribosome and kill drug-resistant Neisseria gonorrhoeae in vivo .
Authors: Zachary D. Aron, Atousa Mehrani, Eric D. Hoffer, Kristie L. Connolly, Matthew C. Torhan, John N. Alumasa, Pooja Srinivas, 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
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W3033366736