 Impact of Ribosomal Modification on the Binding of the Antibiotic Telithromycin Using a Combined Grand Canonical Monte Carlo/Molecular Dynamics Simulation ApproachMeagan C Small, Pedro Lopes, Rodrigo B Andrade and Alexander D MacKerell PLOS Computational Biology, 2013, vol. 9, issue 6, 1-14 Abstract: Resistance to macrolide antibiotics is conferred by mutation of A2058 to G or methylation by Erm methyltransferases of the exocyclic N6 of A2058 (E. coli numbering) that forms the macrolide binding site in the 50S subunit of the ribosome. Ketolides such as telithromycin mitigate A2058G resistance yet remain susceptible to Erm-based resistance. Molecular details associated with macrolide resistance due to the A2058G mutation and methylation at N6 of A2058 by Erm methyltransferases were investigated using empirical force field-based simulations. To address the buried nature of the macrolide binding site, the number of waters within the pocket was allowed to fluctuate via the use of a Grand Canonical Monte Carlo (GCMC) methodology. The GCMC water insertion/deletion steps were alternated with Molecular Dynamics (MD) simulations to allow for relaxation of the entire system. From this GCMC/MD approach information on the interactions between telithromycin and the 50S ribosome was obtained. In the wild-type (WT) ribosome, the 2′-OH to A2058 N1 hydrogen bond samples short distances with a higher probability, while the effectiveness of telithromycin against the A2058G mutation is explained by a rearrangement of the hydrogen bonding pattern of the 2′-OH to 2058 that maintains the overall antibiotic-ribosome interactions. In both the WT and A2058G mutation there is significant flexibility in telithromycin's imidazole-pyridine side chain (ARM), indicating that entropic effects contribute to the binding affinity. Methylated ribosomes show lower sampling of short 2′-OH to 2058 distances and also demonstrate enhanced G2057-A2058 stacking leading to disrupted A752-U2609 Watson-Crick (WC) interactions as well as hydrogen bonding between telithromycin's ARM and U2609. This information will be of utility in the rational design of novel macrolide analogs with improved activity against methylated A2058 ribosomes.Author Summary: Bacterial resistance to antibiotics is a serious public health problem that requires the continuous development of new antibiotics. Bacteria acquire resistance to macrolide antibiotics by (1) effluxing the drug from the cell, (2) modifying the drug, or (3) modifying the drug target (i.e., the 50S subunit of the ribosome) to abrogate or completely abolish binding. While newer antibiotics are able to avoid the first two mechanisms, they remain unable to overcome resistance due to ribosomal modification, particularly due to methyltransferase (i.e., erm) enzymes. We have applied computer-aided drug design methods designed explicitly for studies of the ribosome to better understand the relationship between modification of the ribosome by erms and the binding of telithromycin, a 3rd generation ketolide antibiotic derived from erythromycin. While we confirm that ribosomal modification leads to decreased binding due to disruption of key interactions with the drug, we find these modifications effect a structural rearrangement of the entire region of the ribosome responsible for binding macrolide antibiotics. This information will be useful in the design of novel antibiotics that are effective against resistant bacteria possessing modified ribosomes. Date: 2013 Downloads: (external link) Related works: Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text Persistent link: https://EconPapers.repec.org/RePEc:plo:pcbi00:1003113 DOI: 10.1371/journal.pcbi.1003113 Access Statistics for this article More articles in PLOS Computational Biology from Public Library of Science |
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