@article{ae564c8ec5b142ada5ee2d28d9d54a78,
title = "trans-Translation inhibitors bind to a novel site on the ribosome and clear Neisseria gonorrhoeae in vivo",
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.",
author = "Aron, {Zachary D.} and Atousa Mehrani and Hoffer, {Eric D.} and Connolly, {Kristie L.} and Pooja Srinivas and Torhan, {Matthew C.} and Alumasa, {John N.} and Mynthia Cabrera and Divya Hosangadi and Barbor, {Jay S.} and Cardinale, {Steven C.} and Kwasny, {Steven M.} and Morin, {Lucas R.} and Butler, {Michelle M.} and Opperman, {Timothy J.} and Bowlin, {Terry L.} and Ann Jerse and Stagg, {Scott M.} and Dunham, {Christine M.} and Keiler, {Kenneth C.}",
note = "Funding Information: We are grateful to Shura Mankin for providing bL27 mutants; Tim Murphy and the staff at Neosome Life Sciences LLC for support in performing and evaluating murine tolerability studies; Charles River Labs, for performing murine pharmacokinetic studies; Micromyx for performing MIC90 studies; Eurofins Panlabs, RTI International and SRI Biosciences for performing extensive in vitro safety screening studies. Funding and support for this research was provided by NIH grant R01GM121650 to K.C.K. and by NIAID preclinical contract services, NIH grant R43AI141132 to Z.D.A., and R01AI132276 to Z.D.A., and T32AI106699 to P.S. C.M.D. is a Burroughs Wellcome Fund Investigator in the Pathogenesis of Infectious Disease. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the Department of Defense or the Uniformed Services University. Publisher Copyright: {\textcopyright} 2021, The Author(s).",
year = "2021",
month = dec,
day = "1",
doi = "10.1038/s41467-021-22012-7",
language = "English (US)",
volume = "12",
journal = "Nature communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}