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Odilorhabdins, Antibacterial Agents that Cause Miscoding by Binding at a New Ribosomal Site
Nosopharm, Espace Innovat 2, 110 Allee Charles Babbage, F-30000 Nimes, France.
Univ Illinois, Ctr Biomol Sci, Chicago, IL 60607 USA.
Univ Illinois, Dept Biol Sci, Chicago, IL 60607 USA.
Nosopharm, Espace Innovat 2, 110 Allee Charles Babbage, F-30000 Nimes, France.
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2018 (English)In: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 70, no 1, p. 83-94Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
CELL PRESS , 2018. Vol. 70, no 1, p. 83-94
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-352693DOI: 10.1016/j.molcel.2018.03.001ISI: 000429301100010PubMedID: 29625040OAI: oai:DiVA.org:uu-352693DiVA, id: diva2:1215605
Funder
EU, European Research Council
Available from: 2018-06-08 Created: 2018-06-08 Last updated: 2018-06-08Bibliographically approved

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Huseby, Douglas LHughes, Diarmaid

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