PDBsum entry 6x3c

Transferase

PDB id: 6x3c

Contents

Protein chains

(+ 0 more) 207 a.a.

Ligands

SXA ×6

O7S ×6

PO4 ×14

SO4 ×4

Metals

_CL ×6

_MG ×2

Waters ×44

PDB id:

6x3c

Name:

Transferase

Title:

Crystal structure of streptogramin a acetyltransferase vata from staphylococcus aureus in complex with streptogramin analog f1037 (47)

Structure:

Virginiamycin a acetyltransferase. Chain: a, b, c, d, e, f. Engineered: yes

Source:

Staphylococcus aureus. Organism_taxid: 1280. Gene: vat. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

3.05Å R-factor: 0.234 R-free: 0.266

Authors:

H.A.Chaires,J.S.Fraser

Key ref:

Q.Li et al. (2020). Synthetic group A streptogramin antibiotics that overcome Vat resistance. Nature, 586, 145-150. PubMed id: 32968273 DOI: 10.1038/s41586-020-2761-3

Date:

21-May-20 Release date: 18-Nov-20

Protein chains

P26839  (VATA_STAAU) -  Virginiamycin A acetyltransferase from Staphylococcus aureus

Seq: 219 a.a.

Struc: 207 a.a.

Enzyme reactions

• Enzyme class: E.C.2.3.1.- - ?????

DOI no: 10.1038/s41586-020-2761-3

Nature 586:145-150 (2020)

PubMed id: 32968273

Synthetic group A streptogramin antibiotics that overcome Vat resistance.

Q.Li, J.Pellegrino, D.J.Lee, A.A.Tran, H.A.Chaires, R.Wang, J.E.Park, K.Ji, D.Chow, N.Zhang, A.F.Brilot, J.T.Biel, G.van Zundert, K.Borrelli, D.Shinabarger, C.Wolfe, B.Murray, M.P.Jacobson, E.Mühle, O.Chesneau, J.S.Fraser, I.B.Seiple.

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.