title: Complex long-distance effects of mutations that confer linezolid resistance in the large ribosomal subunit.
abstract: The emergence of multidrug-resistant pathogens will make current antibiotics ineffective. For linezolid, a member of the novel oxazolidinone class of antibiotics, 10 nucleotide mutations in the ribosome have been described conferring resistance. Hypotheses for how these mutations affect antibiotics binding have been derived based on comparative crystallographic studies. However, a detailed description at the atomistic level of how remote mutations exert long-distance effects has remained elusive. Here, we show that the G2032A-C2499A double mutation, located > 10 Å away from the antibiotic, confers linezolid resistance by a complex set of effects that percolate to the binding site. By molecular dynamics simulations and free energy calculations, we identify U2504 and C2452 as spearheads among binding site nucleotides that exert the most immediate effect on linezolid binding. Structural reorganizations within the ribosomal subunit due to the mutations are likely associated with mutually compensating changes in the effective energy. Furthermore, we suggest two main routes of information transfer from the mutation sites to U2504 and C2452. Between these, we observe cross-talk, which suggests that synergistic effects observed for the two mutations arise in an indirect manner. These results should be relevant for the development of oxazolidinone derivatives that are active against linezolid-resistant strains.
authors.affiliation: Institute for Pharmaceutical and Medicinal Chemistry, Department of Mathematics and Natural Sciences, Heinrich-Heine University, Universitätsstrasse 1, 40225 Düsseldorf, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Fulle
authors.affiliation: Institute for Pharmaceutical and Medicinal Chemistry, Department of Mathematics and Natural Sciences, Heinrich-Heine University, Universitätsstrasse 1, 40225 Düsseldorf, Germany.
authors.forename: Jagmohan S
authors.initials: JS
authors.lastname: Saini
authors.affiliation: Institute for Pharmaceutical and Medicinal Chemistry, Department of Mathematics and Natural Sciences, Heinrich-Heine University, Universitätsstrasse 1, 40225 Düsseldorf, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Homeyer
authors.affiliation: Institute for Pharmaceutical and Medicinal Chemistry, Department of Mathematics and Natural Sciences, Heinrich-Heine University, Universitätsstrasse 1, 40225 Düsseldorf, Germany gohlke@uni-duesseldorf.de.
authors.forename: Holger
authors.initials: H
authors.lastname: Gohlke
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry*; D001665:Binding Sites; D024881:Drug Resistance, Bacterial / Q000235:genetics; D000069349:Linezolid / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D009154:Mutation; D009711:Nucleotides / Q000737:chemistry; D023303:Oxazolidinones / Q000737:chemistry; D011500:Protein Synthesis Inhibitors / Q000737:chemistry*; D054748:Ribosome Subunits, Large, Archaeal / Q000737:chemistry* / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D009711:Nucleotides; D023303:Oxazolidinones; D011500:Protein Synthesis Inhibitors; C552047:radezolid; D000069349:Linezolid