8VTV

Crystal structure of the wild-type Thermus thermophilus 70S ribosome in complex with macrolone MCX-91, mRNA, aminoacylated A-site Phe-tRNAphe, aminoacylated P-site fMet-tRNAmet, and deacylated E-site tRNAphe at 2.55A resolution

This is a non-PDB format compatible entry.

Summary for 8VTV

• Entry DOI: 10.2210/pdb8vtv/pdb
• Descriptor: 23S Ribosomal RNA, 50S ribosomal protein L14, 50S ribosomal protein L15, ... (64 entities in total)
• Functional Keywords: macrolone; macrolide; fluoroquinolone; erythromycin; ciprofloxacin; antibiotic; 70s ribosome; x-ray structure; inhibition of translation; peptidyl transferase center; nascent peptide exit tunnel; multidrug; resistance; methylation; 23s rrna; a2058; erm, ribosome
• Biological source: Escherichia coli; More
• Total number of polymer chains: 112
• Total formula weight: 4572452.62

Authors

Aleksandrova, E.V.,Ma, C.-X.,Klepacki, D.,Alizadeh, F.,Vazquez-Laslop, N.,Liang, J.-H.,Polikanov, Y.S.,Mankin, A.S. (deposition date: 2024-01-27, release date: 2024-08-07, Last modification date: 2025-03-19)

Primary citation

Aleksandrova, E.V.,Ma, C.X.,Klepacki, D.,Alizadeh, F.,Vazquez-Laslop, N.,Liang, J.H.,Polikanov, Y.S.,Mankin, A.S.
Macrolones target bacterial ribosomes and DNA gyrase and can evade resistance mechanisms.
Nat.Chem.Biol., 20:1680-1690, 2024

PubMed Abstract: Growing resistance toward ribosome-targeting macrolide antibiotics has limited their clinical utility and urged the search for superior compounds. Macrolones are synthetic macrolide derivatives with a quinolone side chain, structurally similar to DNA topoisomerase-targeting fluoroquinolones. While macrolones show enhanced activity, their modes of action have remained unknown. Here, we present the first structures of ribosome-bound macrolones, showing that the macrolide part occupies the macrolide-binding site in the ribosomal exit tunnel, whereas the quinolone moiety establishes new interactions with the tunnel. Macrolones efficiently inhibit both the ribosome and DNA topoisomerase in vitro. However, in the cell, they target either the ribosome or DNA gyrase or concurrently both of them. In contrast to macrolide or fluoroquinolone antibiotics alone, dual-targeting macrolones are less prone to select resistant bacteria carrying target-site mutations or to activate inducible macrolide resistance genes. Furthermore, because some macrolones engage Erm-modified ribosomes, they retain activity even against strains with constitutive erm resistance genes.

PubMed: 39039256
DOI: 10.1038/s41589-024-01685-3

Experimental method

X-RAY DIFFRACTION (2.55 Å)