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

Autor: Aron ZD; Microbiotix, Inc. One Innovation Dr., Worcester, MA, USA., Mehrani A; Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL, USA., Hoffer ED; Department of Biochemistry and Emory Antibiotic Resistance Center, Emory University School of Medicine, Atlanta, GA, USA., Connolly KL; Department of Microbiology and Immunology, Uniformed Services University, Bethesda, MD, USA., Srinivas P; Department of Biochemistry and Emory Antibiotic Resistance Center, Emory University School of Medicine, Atlanta, GA, USA.; Molecular & Systems Pharmacology Graduate Program, Emory University, Atlanta, GA, USA., Torhan MC; Microbiotix, Inc. One Innovation Dr., Worcester, MA, USA., Alumasa JN; Department of Biochemistry & Molecular Biology, Penn State University, University Park, PA, USA., Cabrera M; Department of Biochemistry & Molecular Biology, Penn State University, University Park, PA, USA., Hosangadi D; Department of Biochemistry & Molecular Biology, Penn State University, University Park, PA, USA., Barbor JS; Microbiotix, Inc. One Innovation Dr., Worcester, MA, USA., Cardinale SC; Microbiotix, Inc. One Innovation Dr., Worcester, MA, USA., Kwasny SM; Microbiotix, Inc. One Innovation Dr., Worcester, MA, USA., Morin LR; Microbiotix, Inc. One Innovation Dr., Worcester, MA, USA., Butler MM; Microbiotix, Inc. One Innovation Dr., Worcester, MA, USA., Opperman TJ; Microbiotix, Inc. One Innovation Dr., Worcester, MA, USA., Bowlin TL; Microbiotix, Inc. One Innovation Dr., Worcester, MA, USA., Jerse A; Department of Microbiology and Immunology, Uniformed Services University, Bethesda, MD, USA., Stagg SM; Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL, USA.; Institute of Molecular Biophysics, Florida State University, Tallahassee, FL, USA., Dunham CM; Department of Biochemistry and Emory Antibiotic Resistance Center, Emory University School of Medicine, Atlanta, GA, USA. cmdunha@emory.edu., Keiler KC; Department of Biochemistry & Molecular Biology, Penn State University, University Park, PA, USA. kkeiler@psu.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2021 Mar 19; Vol. 12 (1), pp. 1799. Date of Electronic Publication: 2021 Mar 19.
DOI: 10.1038/s41467-021-22012-7
Abstrakt: 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.
Databáze: MEDLINE
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