Identifizierung und Charakterisierung von neuen Ribosomen-Antibiotika
Biochemie
Zusammenfassung der Projektergebnisse
The translational machinery is a major target within the cell for antibiotics. The increase in multidrug resistant pathogenic bacteria is making our current arsenal of antibiotics obsolete, highlighting the urgency for the discovery and development of new antibiotics. This DFG-RSF project aimed to discover new compounds that target the ribosome and inhibit translation as well as characterize already known but poorly studied compounds. Together with our collaborators, we report the discovery and characterization of two novel translation inhibitors, tetracenomycin X and auraplanin. Both have novel binding sites on the ribosome and do not appear to exhibit crossresistance with other known clinically-used antibiotics. Moreover, both compounds have novel scaffolds and utilize previously unreported modes of interaction with the ribosome. In addition, we have characterized a variety of other translation inhibitors, including apidaecin, Bac5, mxyovalargin A and B, argyrin B, amino-negamycin, evernimicin-rosamicin and Paenilamicin B2. We believe that by understanding the structural details of the interaction of drugs with the ribosome and the mechanism by which these compounds inhibit translation, we will open new pathways for the development of improved antibiotics to overcome multi-drug resistant pathogenic bacteria.
Projektbezogene Publikationen (Auswahl)
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Fragments of the Nonlytic Proline-Rich Antimicrobial Peptide Bac5 Kill Escherichia coli Cells by Inhibiting Protein Synthesis. Antimicrobial Agents and Chemotherapy, 62(8).
Mardirossian, Mario; Barrière, Quentin; Timchenko, Tatiana; Müller, Claudia; Pacor, Sabrina; Mergaert, Peter; Scocchi, Marco & Wilson, Daniel N.
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The Dolphin Proline-Rich Antimicrobial Peptide Tur1A Inhibits Protein Synthesis by Targeting the Bacterial Ribosome. Cell Chemical Biology, 25(5), 530-539.e7.
Mardirossian, Mario; Pérébaskine, Natacha; Benincasa, Monica; Gambato, Stefano; Hofmann, Sven; Huter, Paul; Müller, Claudia; Hilpert, Kai; Innis, C. Axel; Tossi, Alessandro & Wilson, Daniel N.
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Visualization of translation termination intermediates trapped by the Apidaecin 137 peptide during RF3-mediated recycling of RF1. Nature Communications, 9(1).
Graf, Michael; Huter, Paul; Maracci, Cristina; Peterek, Miroslav; Rodnina, Marina V. & Wilson, Daniel N.
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The Natural Product Elegaphenone Potentiates Antibiotic Effects against Pseudomonas aeruginosa. Angewandte Chemie International Edition, 58(25), 8581-8584.
Zhao, Weining; Cross, Ashley R.; Crowe‐McAuliffe, Caillan; Weigert‐Munoz, Angela; Csatary, Erika E.; Solinski, Amy E.; Krysiak, Joanna; Goldberg, Joanna B.; Wilson, Daniel N.; Medina, Eva; Wuest, William M. & Sieber, Stephan A.
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Bifunctional Nitrone-Conjugated Secondary Metabolite Targeting the Ribosome. Journal of the American Chemical Society, 142(43), 18369-18377.
Limbrick, Emilianne M.; Graf, Michael; Derewacz, Dagmara K.; Nguyen, Fabian; Spraggins, Jeffrey M.; Wieland, Maximiliane; Ynigez-Gutierrez, Audrey E.; Reisman, Benjamin J.; Zinshteyn, Boris; McCulloch, Kathryn M.; Iverson, T. M.; Green, Rachel; Wilson, Daniel N. & Bachmann, Brian O.
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Mechanism of ribosome rescue by alternative ribosome-rescue factor B. Nature Communications, 11(1).
Chan, Kai-Hsin; Petrychenko, Valentyn; Mueller, Claudia; Maracci, Cristina; Holtkamp, Wolf; Wilson, Daniel N.; Fischer, Niels & Rodnina, Marina V.
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Tetracenomycin X inhibits translation by binding within the ribosomal exit tunnel. Nature Chemical Biology, 16(10), 1071-1077.
Osterman, Ilya A.; Wieland, Maximiliane; Maviza, Tinashe P.; Lashkevich, Kseniya A.; Lukianov, Dmitrii A.; Komarova, Ekaterina S.; Zakalyukina, Yuliya V.; Buschauer, Robert; Shiriaev, Dmitrii I.; Leyn, Semen A.; Zlamal, Jaime E.; Biryukov, Mikhail V.; Skvortsov, Dmitry A.; Tashlitsky, Vadim N.; Polshakov, Vladimir I.; Cheng, Jingdong; Polikanov, Yury S.; Bogdanov, Alexey A.; Osterman, Andrei L. ... & Sergiev, Petr V.
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Repurposing tRNAs for nonsense suppression. Nature Communications, 12(1).
Albers, Suki; Beckert, Bertrand; Matthies, Marco C.; Mandava, Chandra Sekhar; Schuster, Raphael; Seuring, Carolin; Riedner, Maria; Sanyal, Suparna; Torda, Andrew E.; Wilson, Daniel N. & Ignatova, Zoya
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Ribosome Rescue Pathways in Bacteria. Frontiers in Microbiology, 12.
Müller, Claudia; Crowe-McAuliffe, Caillan & Wilson, Daniel N.
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Total Synthesis and Biological Evaluation of Paenilamicins from the Honey Bee Pathogen Paenibacillus larvae. Journal of the American Chemical Society, 144(1), 288-296.
Bulatov, Timur; Gensel, Sebastian; Mainz, Andi; Dang, Tam; Koller, Timm O.; Voigt, Kerstin; Ebeling, Julia; Wilson, Daniel N.; Genersch, Elke & Süssmuth, Roderich D.
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The cyclic octapeptide antibiotic argyrin B inhibits translation by trapping EF-G on the ribosome during translocation. Proceedings of the National Academy of Sciences, 119(19).
Wieland, Maximiliane; Holm, Mikael; Rundlet, Emily J.; Morici, Martino; Koller, Timm O.; Maviza, Tinashe P.; Pogorevc, Domen; Osterman, Ilya A.; Müller, Rolf; Blanchard, Scott C. & Wilson, Daniel N.
