Synthetic group A streptogramin antibiotics that overcome Vat resistance

Qi Li, Jenna Pellegrino, D. John Lee, Arthur A. Tran, Hector A. Chaires, Ruoxi Wang, Jesslyn E. Park, Kaijie Ji, David Chow, Na Zhang, Axel F. Brilot, Justin T. Biel, Gydo Zundert, Kenneth Borrelli, Dean Shinabarger, Cindy Wolfe, Beverly Murray, Matthew P. Jacobson, Estelle Mühle, Olivier Chesneau, James S. Fraser and Ian B. Seiple ()
Additional contact information
Qi Li: University of California, San Francisco
Jenna Pellegrino: University of California, San Francisco
D. John Lee: University of California, San Francisco
Arthur A. Tran: University of California, San Francisco
Hector A. Chaires: University of California, San Francisco
Ruoxi Wang: University of California, San Francisco
Jesslyn E. Park: University of California, San Francisco
Kaijie Ji: University of California, San Francisco
David Chow: University of California, San Francisco
Na Zhang: University of California, San Francisco
Axel F. Brilot: University of California, San Francisco
Justin T. Biel: University of California, San Francisco
Gydo Zundert: Schrödinger
Kenneth Borrelli: University of California, San Francisco
Dean Shinabarger: Micromyx
Cindy Wolfe: Micromyx
Beverly Murray: Micromyx
Matthew P. Jacobson: University of California, San Francisco
Estelle Mühle: Institut Pasteur
Olivier Chesneau: Institut Pasteur
James S. Fraser: University of California, San Francisco
Ian B. Seiple: University of California, San Francisco

Nature, 2020, vol. 586, issue 7827, 145-150

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-020-2761-3

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