8FC5

Crystal structure of the A2058-N6-dimethylated Thermus thermophilus 70S ribosome in complex with protein Y, hygromycin A, and azithromycin at 2.65A resolution

This is a non-PDB format compatible entry.

Summary for 8FC5

• Entry DOI: 10.2210/pdb8fc5/pdb
• Descriptor: 23S Ribosomal RNA, 50S ribosomal protein L14, 50S ribosomal protein L15, ... (61 entities in total)
• Functional Keywords: hygromycin a; macrolides; ketolides; erythromycin; azithromycin; telithromycin; antibiotic; synergy; erm methyltransferase, x-ray structure; 70s ribosome; peptidyl transferase center; nascent peptide exit tunnel, ribosome
• Biological source: Escherichia coli; More
• Total number of polymer chains: 106
• Total formula weight: 4427716.79

Authors

Chen, C.-W.,Syroegin, E.A.,Svetlov, M.S.,Polikanov, Y.S. (deposition date: 2022-12-01, release date: 2023-07-26)

Primary citation

Chen, C.W.,Leimer, N.,Syroegin, E.A.,Dunand, C.,Bulman, Z.P.,Lewis, K.,Polikanov, Y.S.,Svetlov, M.S.
Structural insights into the mechanism of overcoming Erm-mediated resistance by macrolides acting together with hygromycin-A.
Nat Commun, 14:4196-4196, 2023

PubMed Abstract: The ever-growing rise of antibiotic resistance among bacterial pathogens is one of the top healthcare threats today. Although combination antibiotic therapies represent a potential approach to more efficiently combat infections caused by susceptible and drug-resistant bacteria, only a few known drug pairs exhibit synergy/cooperativity in killing bacteria. Here, we discover that well-known ribosomal antibiotics, hygromycin A (HygA) and macrolides, which target peptidyl transferase center and peptide exit tunnel, respectively, can act cooperatively against susceptible and drug-resistant bacteria. Remarkably, HygA slows down macrolide dissociation from the ribosome by 60-fold and enhances the otherwise weak antimicrobial activity of the newest-generation macrolide drugs known as ketolides against macrolide-resistant bacteria. By determining a set of high-resolution X-ray crystal structures of drug-sensitive wild-type and macrolide-resistant Erm-methylated 70S ribosomes in complex with three HygA-macrolide pairs, we provide a structural rationale for the binding cooperativity of these drugs and also uncover the molecular mechanism of overcoming Erm-type resistance by macrolides acting together with hygromycin A. Altogether our structural, biochemical, and microbiological findings lay the foundation for the subsequent development of synergistic antibiotic tandems with improved bactericidal properties against drug-resistant pathogens, including those expressing erm genes.

PubMed: 37452045
DOI: 10.1038/s41467-023-39653-5

Experimental method

X-RAY DIFFRACTION (2.65 Å)