DSSR-PyMOL cartoon-block schematics: PDB entry 6pct

PDB-id

6pct; SNAP-derived features in text and JSON formats

Class

ribosome

Method

cryo-EM (2.8 Å)

Summary

E. coli 50s ribosome bound to compound 41q

Reference

Li Q, Pellegrino J, Lee DJ, Tran AA, Chaires HA, Wang R, Park JE, Ji K, Chow D, Zhang N, Brilot AF, Biel JT, van Zundert G, Borrelli K, Shinabarger D, Wolfe C, Murray B, Jacobson MP, Muhle E, Chesneau O, Fraser JS, Seiple IB (2020): "Synthetic group A streptogramin antibiotics that overcome Vat resistance." Nature, 586, 145-150. doi: 10.1038/s41586-020-2761-3.

Abstract

Natural products serve as chemical blueprints for most antibiotics in clinical use. The evolutionary process by which these molecules arise is inherently accompanied by the co-evolution of resistance mechanisms that shorten the clinical lifetime of any given class of antibiotics₁. Virginiamycin acetyltransferase (Vat) enzymes are resistance proteins that provide protection against streptogramins₂, potent antibiotics against Gram-positive bacteria that inhibit the bacterial ribosome₃. Owing to the challenge of selectively modifying the chemically complex, 23-membered macrocyclic scaffold of group A streptogramins, analogues that overcome the resistance conferred by Vat enzymes have not been previously developed₂. Here we report the design, synthesis, and antibacterial evaluation of group A streptogramin antibiotics with extensive structural variability. Using cryo-electron microscopy and forcefield-based refinement, we characterize the binding of eight analogues to the bacterial ribosome at high resolution, revealing binding interactions that extend into the peptidyl tRNA-binding site and towards synergistic binders that occupy the nascent peptide exit tunnel. One of these analogues has excellent activity against several streptogramin-resistant strains of Staphylococcus aureus, exhibits decreased rates of acetylation in vitro, and is effective at lowering bacterial load in a mouse model of infection. Our results demonstrate that the combination of rational design and modular chemical synthesis can revitalize classes of antibiotics that are limited by naturally arising resistance mechanisms.