ArticlePLoS computational biology2013
Impact of ribosomal modification on the binding of the antibiotic telithromycin using a combined grand canonical monte carlo/molecular dynamics simulation approach.
Article in PLoS computational biology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed.
- The Complexity of erm-Mediated Resistance: Structural and Functional Perspectives From β-Hemolytic Streptococci.Molecular microbiology · 2026Review
- A multi-stage computational pipeline andRSC advances · 2026Article
- A Computationally Efficient Method to Generate Plausible Conformers for Ensemble Docking and Binding Free Energy Calculations.Journal of chemical information and modeling · 2025Article
- Machines on Genes through the Computational Microscope.Journal of chemical theory and computation · 2023Review
- Structure of Erm-modified 70S ribosome reveals the mechanism of macrolide resistance.Nature chemical biology · 2021Article
- Advanced Methods for Studying Structure and Interactions of Macrolide Antibiotics.International journal of molecular sciences · 2020Review
- Molecular dynamics simulations suggest why the A2058G mutation in 23S RNA results in bacterial resistance against clindamycin.Journal of molecular modeling · 2018Article
- Computer-Aided Drug Design Methods.Methods in molecular biology (Clifton, N.J.) · 2017Article
- Parametrization of macrolide antibiotics using the force field toolkit.Journal of computational chemistry · 2015Article
- CHARMM additive and polarizable force fields for biophysics and computer-aided drug design.Biochimica et biophysica acta · 2015Review
- Molecular dynamics simulations of large macromolecular complexes.Current opinion in structural biology · 2015Review
- Desmethyl macrolides: synthesis and evaluation of 4-desmethyl telithromycin.ACS medicinal chemistry letters · 2014Article
- Sampling of Organic Solutes in Aqueous and Heterogeneous Environments Using Oscillating Excess Chemical Potentials in Grand Canonical-like Monte Carlo-Molecular Dynamics Simulations.Journal of chemical theory and computation · 2014Article
- Desmethyl Macrolides: Synthesis and Evaluation of 4,8,10-Tridesmethyl Cethromycin.ACS medicinal chemistry letters · 2013Article
Corrections and comments
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Authors and funding
4 authors.
Funding
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.
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