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.
Subject(s)
Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Bacterial Proteins/biosynthesis , DNA, Bacterial/genetics , Klebsiella Infections/drug therapy , Ribosome Subunits, Small/drug effects , Xenorhabdus/metabolism , Aminoacyltransferases/genetics , Aminoacyltransferases/metabolism , Animals , Anti-Bacterial Agents/metabolism , Bacteria/genetics , Bacteria/metabolism , Bacterial Proteins/genetics , Binding Sites , Disease Models, Animal , Female , Hep G2 Cells , Humans , Klebsiella Infections/microbiology , Klebsiella pneumoniae/drug effects , Klebsiella pneumoniae/genetics , Klebsiella pneumoniae/metabolism , Male , Mice, Inbred ICR , Protein Biosynthesis/drug effects , Ribosome Subunits, Small/genetics , Ribosome Subunits, Small/metabolismABSTRACT
The spread of antibiotic-resistant pathogens is a growing concern, and new families of antibacterials are desperately needed. Odilorhabdins are a new class of antibacterial compounds that bind to the bacterial ribosome and kill bacteria through inhibition of the translation. NOSO-95C, one of the first member of this family, was synthesized for the first time, and then a structure-activity relationships study was performed to understand which groups are important for antibacterial activity and for inhibition of the bacterial translation. Based on this study an analogue showing improved properties compared to the parent compound was identified and showed promising in vitro and in vivo efficacy against Enterobacteriaceae.