Odilorhabdins, Antibacterial Agents that Cause Miscoding by Binding at a New Ribosomal Site
2 UIC - University of Illinois [Chicago]
3 Department of Biological Sciences [Chicago]
4 ICGM - Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier
5 DGIMI - Diversité, Génomes & Interactions Microorganismes - Insectes [Montpellier]
6 Department of Biological Sciences [Milwaukee]
7 IRBA - Institut de Recherche Biomédicale des Armées [Antenne Marseille]
8 MCT - Membranes et cibles thérapeutiques
9 Statens Serum Institut [Copenhagen]
10 Department of Medical Biochemistry and Microbiology
11 Department of Medicinal Chemistry and Pharmacognosy
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Résumé
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.