Odilorhabdins, Antibacterial Agents that Cause Miscoding by Binding at a New Ribosomal Site
| Autor: | Alexander S. Mankin, Jean-Marc Campagne, Tanja Florin, Camille Midrier, Emilie Racine, Marine Serri, Maxime Gualtieri, Steve Forst, Malgorzata Dobosz-Bartoszek, André Aumelas, Sophie Gaudriault, Diarmaid Hughes, Matthieu Sarciaux, Philippe Villain-Guillot, Jessica Houard, Yury S. Polikanov, Jean-Michel Bolla, Carina Vingsbo Lundberg, Douglas L. Huseby, Christelle Cotteaux-Lautard, Lucile Pantel, Renata Marcia de Figueiredo, Anne Lanois, Alain Givaudan |
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| Přispěvatelé: | Nosopharm, University of Illinois [Chicago] (UIC), University of Illinois System, Department of Biological Sciences [Chicago], University of Illinois System-University of Illinois System, Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM ICMMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut de Chimie du CNRS (INC), Diversité, Génomes & Interactions Microorganismes - Insectes [Montpellier] (DGIMI), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM), Department of Biological Sciences [Milwaukee], University of Wisconsin - Milwaukee, Institut de Recherche Biomédicale des Armées [Antenne Marseille] (IRBA), Membranes et cibles thérapeutiques (MCT), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées (IRBA), Statens Serum Institut [Copenhagen], Department of Medical Biochemistry and Microbiology, Uppsala University, Department of Medicinal Chemistry and Pharmacognosy, National Institute of General Medical Sciences from the NIH [P41 GM103403], NIH-ORIP HEI grant [S10 RR029205, S10 OD021527], DOE Office of Science [DE-AC02-06CH11357], OSEO [A1010014J], Region Languedoc-Roussillon [A1010014J], DGA [122906117], Innovative Medicines Initiative Joint Undertaking [115583], Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
DNA
Bacterial Male 0301 basic medicine medicine.drug_class 030106 microbiology Antibiotics Biology medicine.disease_cause Ribosome Xenorhabdus Article Bacterial genetics Microbiology 03 medical and health sciences Bacterial Proteins medicine Animals Humans Molecular Biology Mice Inbred ICR Binding Sites Bacteria [CHIM.ORGA]Chemical Sciences/Organic chemistry Pathogenic bacteria Hep G2 Cells Cell Biology Ribosomal RNA Aminoacyltransferases biology.organism_classification Enterobacteriaceae Anti-Bacterial Agents Klebsiella Infections Ribosome Subunits Small 3. Good health Disease Models Animal Klebsiella pneumoniae A-site 030104 developmental biology Protein Biosynthesis Female |
| Zdroj: | Molecular Cell Molecular Cell, Elsevier, 2018, 70 (1), pp.83-94. ⟨10.1016/j.molcel.2018.03.001⟩ Molecular Cell, 2018, 70 (1), pp.83-94. ⟨10.1016/j.molcel.2018.03.001⟩ |
| ISSN: | 1097-2765 1097-4164 |
| Popis: | International audience; Growing resistance of pathogenic bacteria and shortage of antibiotic discovery platforms challenge the use of antibiotics in the clinic. This threat calls for exploration of unconventional sources of antibiotics and identification of inhibitors able to eradicate resistant bacteria. Here we describe a different class of antibiotics, odilorhabdins (ODLs), produced by the enzymes of the non-ribosomal peptide synthetase gene cluster of the nematode-symbiotic bacterium Xenorhabdus nematophila. ODLs show activity against Gram-positive and Gram-negative pathogens, including carbapenem-resistant Enterobacteriaceae, and can eradicate infections in animal models. We demonstrate that the bactericidal ODLs interfere with protein synthesis. Genetic and structural analyses reveal that ODLs bind to the small ribosomal subunit at a site not exploited by current antibiotics. ODLs induce miscoding and promote hungry codon readthrough, amino acid misincorporation, and premature stop codon bypass. We propose that ODLs' miscoding activity reflects their ability to increase the affinity of non-cognate aminoacyl-tRNAs to the ribosome. |
| Databáze: | OpenAIRE |
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