Determinants of the species selectivity of oxazolidinone antibiotics targeting the large ribosomal subunit

Abstract

Oxazolidinone antibiotics bind to the highly conserved peptidyl transferase center in the ribosome. For developing selective antibiotics, a profound understanding of the selectivity determinants is required. We have performed for the first time technically challenging molecular dynamics simulations in combination with molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) free energy calculations of the oxazolidinones linezolid and radezolid bound to the large ribosomal subunits of the eubacterium Deinococcus radiodurans and the archaeon Haloarcula marismortui. A remarkably good agreement of the computed relative binding free energy with selectivity data available from experiment for linezolid is found. On an atomic level, the analyses reveal an intricate interplay of structural, energetic, and dynamic determinants of the species selectivity of oxazolidinone antibiotics: A structural decomposition of free energy components identifies influences that originate from first and second shell nucleotides of the binding sites and lead to (opposing) contributions from interaction energies, solvation, and entropic factors. These findings add another layer of complexity to the current knowledge on structure-activity relationships of oxazolidinones binding to the ribosome and suggest that selectivity analyses solely based on structural information and qualitative arguments on interactions may not reach far enough. The computational analyses presented here should be of sufficient accuracy to fill this gap.

Complex long-distance effects of mutations that confer linezolid resistance in the large ribosomal subunit

“…Starting structures for the MD simulations were generated based on the X-ray structure of linezolid in complex with the large ribosomal subunit of H. marismortui (H50S) (PDB code 3CPW) solved at a resolution of 2.7 Å ( 7 , 8 ). Details of the setup and simulation of the wild-type structure (linezolid-H50S wt ) have been described before ( 14 ). To investigate the influence of the G2032A-C2499A double mutation on linezolid binding, a model structure (linezolid-H50S mut ) was generated from the linezolid-H50S wt crystal complex structure by mutating G2032 and C2499 to adenine, respectively.…”

“…To gain insights at an atomistic level into how remote mutations exert long-distance effects that lead to resistance to oxazolidinones, we extended a previous study on the determinants of the species selectivity of oxazolidinone antibiotics, which had considered the wild-type structure of H50S (linezolid-H50S wt ), ( 14 ) by performing molecular dynamics (MD) simulations in combination with molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) free energy calculations of linezolid bound to the double mutant G2032A-C2499A of H50S (linezolid-H50S mut ). Furthermore, MD simulations of two novel oxazolidinone antibiotics, radezolid and tedizolid, that show activity against linezolid-resistant strains, ( 15 ) are performed.…”

Interpreting Thermodynamic Profiles of Aminoadamantane Compounds Inhibiting the M2 Proton Channel of Influenza A by Free Energy Calculations

“…individual entropy contributions were calculated by quasi-harmonic (QH) analysis (S T,R,V, lig in com , S V, rec in com , S V, free rec , S V, free lig ), similar to a scheme recently applied by us 84 …”

New developments in the management of severe skin and deep skin structure infections – focus on tedizolid

“… 21 Second, both agents share the same mechanism of action: binding to the highly conserved, peptidyl transferase A-site of ribosomal ribonucleic acid (rRNA), thus inhibiting protein synthesis. 22 Third, both agents have high oral bioavailability (86%–100%), allowing for oral step-down therapy. 23 – 25 Fourth, the efficacy of both agents is not dependent upon the peak concentration of drug (like aminoglycosides) or the time bacteria are exposed above the minimal inhibitory concentration (like beta-lactams).…”