Structures of MLSBK Antibiotics Bound to Mutated Large Ribosomal Subunits Provide a Structural Explanation for Resistance

@article{Tu2005StructuresOM,
  title={Structures of MLSBK Antibiotics Bound to Mutated Large Ribosomal Subunits Provide a Structural Explanation for Resistance},
  author={Daqi Tu and Gregor Blaha and Peter B Moore and Thomas A. Steitz},
  journal={Cell},
  year={2005},
  volume={121},
  pages={257-270}
}
Crystal structures of H. marismortui large ribosomal subunits containing the mutation G2099A (A2058 in E. coli) with erythromycin, azithromycin, clindamycin, virginiamycin S, and telithromycin bound explain why eubacterial ribosomes containing the mutation A2058G are resistant to them. Azithromycin binds almost identically to both G2099A and wild-type subunits, but the erythromycin affinity increases by more than 10(4)-fold, implying that desolvation of the N2 of G2099 accounts for the low wild… Expand
The structures of antibiotics bound to the E site region of the 50 S ribosomal subunit of Haloarcula marismortui: 13-deoxytedanolide and girodazole.
TLDR
Crystal structures of the 50 S ribosomal subunit from Haloarcula marismortui complexed with two antibiotics have identified new sites at which antibiotics interact with the ribosome and inhibit protein synthesis, and Girodazole is specific for eukarytes and archaea because it makes interactions with L15 that are not possible in eubacteria. Expand
Mutations outside the anisomycin-binding site can make ribosomes drug-resistant.
Eleven mutations that make Haloarcula marismortui resistant to anisomycin, an antibiotic that competes with the amino acid side chains of aminoacyl tRNAs for binding to the A-site cleft of the largeExpand
23S rRNA 2058A→G Alteration Mediates Ketolide Resistance in Combination with Deletion in L22
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Molecular modeling shows that the telithromycin carbamate group is located in the proximity of the tip of the L22 hairpin-loop, allowing for weak interactions between them, and the deletion of 15 residues from protein L22 may further destabilize telitromycin binding and confer telithomorphcin resistance. Expand
Structure of Erm-modified 70S ribosome reveals the mechanism of macrolide resistance.
TLDR
High-resolution structures of two macrolide antibiotics bound to the unmodified ribosome reveal a previously unknown role of the desosamine moiety in drug binding, laying a foundation for the rational knowledge-based design of macrolides that can overcome Erm-mediated resistance. Expand
Insights into the improved macrolide inhibitory activity from the high-resolution cryo-EM structure of dirithromycin bound to the E. coli 70S ribosome.
TLDR
The structure of the dirithromycin bound to the translating Escherichia coli 70S ribosome is determined, which suggests that the better inhibitory properties of the drug could be rationalized by the side chain of dirathromycin pointing into the lumen of the nascent peptide exit tunnel, where it can interfere with the normal passage of the growing polypeptide chain. Expand
Structures of the Escherichia coli ribosome with antibiotics bound near the peptidyl transferase center explain spectra of drug action
TLDR
X-ray crystal structures of the Escherichia coli ribosome in complexes with clinically important antibiotics of four major classes are reported, arguing that the identity of nucleotides 752, 2609, and 2055 of 23S ribosomal RNA explain in part the spectrum and selectivity of antibiotic action. Expand
Mutation from guanine to adenine in 25S rRNA at the position equivalent to E. coli A2058 does not confer erythromycin sensitivity in Sacchromyces cerevisae.
TLDR
The results suggest that the identity of nucleotide 2058 is not the only determinant responsible for the difference in erythromycin sensitivity between yeast and prokaryotes. Expand
Stepwise Binding of Tylosin and Erythromycin to Escherichia coli Ribosomes, Characterized by Kinetic and Footprinting Analysis*
TLDR
The results emphasize the role of the particular interactions that side chains of tylosin and erythromycin establish with 23 S rRNA, which govern the exact binding process of each drug and its response to the ionic environment. Expand
Impact of Ribosomal Modification on the Binding of the Antibiotic Telithromycin Using a Combined Grand Canonical Monte Carlo/Molecular Dynamics Simulation Approach
TLDR
Information was obtained on the interactions between telithromycin and the 50S ribosome that will be of utility in the rational design of novel macrolide analogs with improved activity against methylated A2058 ribosomes. Expand
The structure of ribosome-lankacidin complex reveals ribosomal sites for synergistic antibiotics
TLDR
At least two pairs of structurally dissimilar compounds have been selected in the course of evolution to act synergistically by targeting neighboring sites in the ribosome by binding at the peptidyl transferase center of the eubacterial large ribosomal subunit. Expand
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References

SHOWING 1-10 OF 64 REFERENCES
Structures of five antibiotics bound at the peptidyl transferase center of the large ribosomal subunit.
TLDR
Structures of anisomycin, chloramphenicol, sparsomycin), blasticidin S, and virginiamycin M bound to the large ribosomal subunit of Haloarcula marismortui have been determined at 3.0A resolution, consistent with their functioning as competitive inhibitors of peptide bond formation. Expand
A ketolide resistance mutation in domain II of 23S rRNA reveals the proximity of hairpin 35 to the peptidyl transferase centre
Ketolides represent a new generation of macrolide antibiotics. In order to identify the ketolide‐binding site on the ribosome, a library of Escherichia coli clones, transformed with a plasmidExpand
Erythromycin resistance mutations in ribosomal proteins L22 and L4 perturb the higher order structure of 23 S ribosomal RNA.
TLDR
The hypothesis that ribosomal proteins interact with rRNA at multiple sites to establish its functionally active three-dimensional structure is supported, and it is suggested that these antibiotic resistance mutations act by perturbing the conformation of rRNA. Expand
Binding Site of Macrolide Antibiotics on the Ribosome: New Resistance Mutation Identifies a Specific Interaction of Ketolides with rRNA
TLDR
The location of the macrolide binding site in the nascent peptide exit tunnel at some distance from the peptidyl transferase center agrees with the proposed model of macrolides inhibitory action and explains the dominant nature of macolide resistance mutations. Expand
The structures of four macrolide antibiotics bound to the large ribosomal subunit.
Crystal structures of the Haloarcula marismortui large ribosomal subunit complexed with the 16-membered macrolide antibiotics carbomycin A, spiramycin, and tylosin and a 15-membered macrolide,Expand
The role of rRNA bases in the interaction of peptidyltransferase inhibitors with bacterial ribosomes.
TLDR
Induction by VM of a high affinity VS binding site in VS-sensitive and -resistant ribosomes indicates A2058 mutation to entail a conformational change of this site, which is counteracted by VM fixation. Expand
The macrolide–ketolide antibiotic binding site is formed by structures in domains II and V of 23S ribosomal RNA
TLDR
Findings indicate how drug derivatization can improve the inhibition of bacteria that have macrolide resistance conferred by changes in the peptidyl transferase loop. Expand
Structural basis for the interaction of antibiotics with the peptidyl transferase centre in eubacteria
TLDR
The details of antibiotic interactions with the components of their binding sites are reported and the importance of putative Mg+2 ions for the binding of some drugs is shown to facilitate rational drug design. Expand
Resistance to Quinupristin-Dalfopristin Due to Mutation of L22 Ribosomal Protein in Staphylococcus aureus
TLDR
Synergistic ribosomal binding of streptogramins A and B, studied by analyzing the fluorescence kinetics of pristinamycin IA-ribosome complexes, was abolished in the mutant strain, providing an explanation for quinupristin-dalfopristin resistance. Expand
The in vitro binding of virginiamycin M to bacterial ribosomes and ribosomal subunits
SummaryVirginiamycin M (VM), an antibiotic of type A synergimycin group of antibiotics, binds to bacterial ribosomes and subunits in vitro: the amount of linked drug is linearly dependent on ribosomeExpand
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