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

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 () and Kenneth C. Keiler ()
Additional contact information
Zachary D. Aron: Microbiotix, Inc. One Innovation Dr.
Atousa Mehrani: Florida State University
Eric D. Hoffer: Emory University School of Medicine
Kristie L. Connolly: Uniformed Services University
Pooja Srinivas: Emory University School of Medicine
Matthew C. Torhan: Microbiotix, Inc. One Innovation Dr.
John N. Alumasa: Penn State University
Mynthia Cabrera: Penn State University
Divya Hosangadi: Penn State University
Jay S. Barbor: Microbiotix, Inc. One Innovation Dr.
Steven C. Cardinale: Microbiotix, Inc. One Innovation Dr.
Steven M. Kwasny: Microbiotix, Inc. One Innovation Dr.
Lucas R. Morin: Microbiotix, Inc. One Innovation Dr.
Michelle M. Butler: Microbiotix, Inc. One Innovation Dr.
Timothy J. Opperman: Microbiotix, Inc. One Innovation Dr.
Terry L. Bowlin: Microbiotix, Inc. One Innovation Dr.
Ann Jerse: Uniformed Services University
Scott M. Stagg: Florida State University
Christine M. Dunham: Emory University School of Medicine
Kenneth C. Keiler: Penn State University

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-22012-7

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