title: Activation of the glmS Ribozyme Confers Bacterial Growth Inhibition.
abstract: The ever-growing number of pathogenic bacteria resistant to treatment with antibiotics call for the development of novel compounds with as-yet unexplored modes of action. Here, we demonstrate the in vivo antibacterial activity of carba-α-d-glucosamine (CGlcN). In this mode of action study, we provide evidence that CGlcN-mediated growth inhibition is due to glmS ribozyme activation, and we demonstrate that CGlcN hijacks an endogenous activation pathway, hence utilizing a prodrug mechanism. This is the first report describing antibacterial activity mediated by activating the self-cleaving properties of a ribozyme. Our results open the path towards a compound class with an entirely novel and distinct molecular mechanism.
authors.affiliation: University of Bonn, LIMES Institute, Gerhard-Domagk-Strasse 1, 53121, Bonn, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Schüller
authors.affiliation: University of Bonn, LIMES Institute, Gerhard-Domagk-Strasse 1, 53121, Bonn, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Matzner
authors.affiliation: University of Bonn, LIMES Institute, Gerhard-Domagk-Strasse 1, 53121, Bonn, Germany.|University of Leipzig, Institute for Biochemistry, Brüderstrasse 34, 04103, Leipzig, Germany.
authors.forename: Christina E
authors.initials: CE
authors.lastname: Lünse
authors.affiliation: University of Konstanz, Chemistry Department, Universitaetsstrasse 10, 78464, Konstanz, Germany.
authors.forename: Valentin
authors.identifier: 0000-0003-4043-6813
authors.initials: V
authors.lastname: Wittmann
authors.affiliation: University of Düsseldorf, Institute for Pharmaceutical Biology, Universitätsstrasse 1, Bld. 26.23, Room 00.44, 40225, Düsseldorf, Germany.
authors.forename: Catherine
authors.initials: C
authors.lastname: Schumacher
authors.affiliation: University of Tübingen, Interfaculty Institute for Microbiology and Infection Medicine, Department of Microbiology & Biotechnology, Auf der Morgenstelle 28, 72076, Tübingen, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Unsleber
authors.affiliation: University of Tübingen, Interfaculty Institute for Microbiology and Infection Medicine, Department of Microbial Bioactive Compounds, Auf der Morgenstelle 28, 72076, Tübingen, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Brötz-Oesterhelt
authors.affiliation: University of Tübingen, Interfaculty Institute for Microbiology and Infection Medicine, Department of Microbiology & Biotechnology, Auf der Morgenstelle 28, 72076, Tübingen, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Mayer
authors.affiliation: University of Bonn, Institute of Medical Microbiology, Immunology and Parasitology, Sigmund-Freud-Strasse 25, 53127, Bonn, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Bierbaum
authors.affiliation: University of Bonn, LIMES Institute, Gerhard-Domagk-Strasse 1, 53121, Bonn, Germany.
authors.forename: Günter
authors.identifier: 0000-0003-3010-4049
authors.initials: G
authors.lastname: Mayer
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001412:Bacillus subtilis / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D003511:Cyclohexanols / Q000737:chemistry*; D003514:Cyclohexylamines / Q000737:chemistry*; D004789:Enzyme Activation / Q000187:drug effects; D005944:Glucosamine / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D009154:Mutation; D016337:RNA, Catalytic / Q000235:genetics / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D003511:Cyclohexanols; D003514:Cyclohexylamines; D016337:RNA, Catalytic; C000621303:carbaglucosamine; D005944:Glucosamine
keywords: RNA; antibiotics; hydrolysis; ribozymes