Odilorhabdins, Antibacterial Agents that Cause Miscoding by Binding at a New Ribosomal Site - Archive ouverte HAL Access content directly
Journal Articles Molecular Cell Year : 2018

Odilorhabdins, Antibacterial Agents that Cause Miscoding by Binding at a New Ribosomal Site

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Lucile Pantel
  • Function : Author
  • PersonId : 1024917
Emilie Racine
  • Function : Author
Matthieu Sarciaux
  • Function : Author
Marine Serri
  • Function : Author
Jessica Houard
  • Function : Author
André Aumelas
  • Function : Author
Maxime Gualtieri
  • Function : Author
  • PersonId : 1031530

Abstract

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.

Dates and versions

hal-01761351 , version 1 (09-04-2018)

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Lucile Pantel, Tanja Florin, Malgorzata Dobosz-Bartoszek, Emilie Racine, Matthieu Sarciaux, et al.. Odilorhabdins, Antibacterial Agents that Cause Miscoding by Binding at a New Ribosomal Site. Molecular Cell, 2018, 70 (1), pp.83 - 94. ⟨10.1016/j.molcel.2018.03.001⟩. ⟨hal-01761351⟩
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