Redefining the mode of inhibition by macrolide antibiotics
Macrolide antibiotics, including erythromycin, are widely used in the clinical setting due to their broad-spectrum activity against both Gram-positive and Gram-negative bacteria. In general terms, the inhibitory capacity of macrolide antibiotics is based upon their ability to arrest bacterial growth by interfering with the protein synthesis machinery.
Until recently, the mode of inhibition by macrolide antibiotics was thought to be based upon their ability to indiscriminately impede the passage of newly synthesized polypeptides through the exit channel of the ribosome. Furthermore, this theory has been supported by findings that demonstrate that treatment of cells with macrolide antibiotics leads to a rapid decline in protein synthesis and accumulation of peptidyl-tRNA. However, this widely accepted mechanism does not explain how this particular class of antibiotic can have differential inhibitory affects that depend upon the specific protein being synthesized. In addition, X-ray crystallography studies have demonstrated that, whilst macrolides do cause significant narrowing of the ribosomal nascent peptide exit tunnel, there is still sufficient room for passage of the growing peptide chain. This has raised the question of whether or not some proteins might be able to bypass the bound antibiotic and remain unimpeded by the constriction.
Subsequently, Kannan and colleagues have used genome wide ribosome profiling to show that the mode of macrolide inhibition is actually based upon a more selective inhibition of peptide bond formation between specific combinations of donor aminoacyl-tRNAs and the C-terminus of acceptor amino acids. Therefore, macrolides may be redefined as context- or protein-specific inhibitors of translation. Strikingly, this enhancement in our understanding of the precise mechanism of macrolide inhibition could lead to the development of superior antibiotics that have the capacity to evade common bacterial resistance mechanisms.
Original Research paper: The General mode of translation inhibition by macrolide antibiotics. Kannan et al. Proc Natl Acad Sci USA. 2014 Nov 11; 111(45): 15958-63.
Image source: “Peptide syn” by Boumphreyfr – Own work. Licensed under CC BY-SA 3.0 via Wikimedia Commons – http://commons.wikimedia.org/wiki/File:Peptide_syn.png
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