Odilorhabdins, Antibacterial Agents that Cause Miscoding by Binding at a New Ribosomal Site. Mol Cell 2018 Apr 05;70(1):83-94.e7
Date
04/07/2018Pubmed ID
29625040DOI
10.1016/j.molcel.2018.03.001Scopus ID
2-s2.0-85044901496 (requires institutional sign-in at Scopus site) 78 CitationsAbstract
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.
Author List
Pantel L, Florin T, Dobosz-Bartoszek M, Racine E, Sarciaux M, Serri M, Houard J, Campagne JM, de Figueiredo RM, Midrier C, Gaudriault S, Givaudan A, Lanois A, Forst S, Aumelas A, Cotteaux-Lautard C, Bolla JM, Vingsbo Lundberg C, Huseby DL, Hughes D, Villain-Guillot P, Mankin AS, Polikanov YS, Gualtieri MAuthor
Steven Forst PhD Professor in the Biological Sciences department at University of Wisconsin - MilwaukeeMESH terms used to index this publication - Major topics in bold
AminoacyltransferasesAnimals
Anti-Bacterial Agents
Bacteria
Bacterial Proteins
Binding Sites
DNA, Bacterial
Disease Models, Animal
Female
Hep G2 Cells
Humans
Klebsiella Infections
Klebsiella pneumoniae
Male
Mice, Inbred ICR
Protein Biosynthesis
Ribosome Subunits, Small
Xenorhabdus