Structural basis of Synercid (quinupristin-dalfopristin) resistance in Gram-positive bacterial pathogens.

Abstract

Synercid, a new semisynthetic streptogramin-derived antibiotic containing dalfopristin and quinupristin, is used in treatment of life-threatening infections caused by glycopeptide-resistant Enterococcus faecium and other bacterial pathogens. However, dissemination of genes encoding virginiamycin acetyltransferases, enzymes that confer resistance to streptogramins, threatens to limit the medical utility of the quinupristin-dalfopristin combination. Here we present structures of virginiamycin acetyltransferase D (VatD) determined at 1.8 A resolution in the absence of ligands, at 2.8 A resolution bound to dalfopristin, and at 3.0 A resolution in the presence of acetyl-coenzyme A. Dalfopristin is bound by VatD in a similar conformation to that described previously for the streptogramin virginiamycin M1. However, specific interactions with the substrate are altered as a consequence of a conformational change in the pyrollidine ring that is propagated to adjacent constituents of the dalfopristin macrocycle. Inactivation of dalfopristin involves acetyl transfer from acetyl-coenzyme A to the sole (O-18) hydroxy group of the antibiotic that lies close to the side chain of the strictly conserved residue, His-82. Replacement of residue 82 by alanine is accompanied by a fall in specific activity of >105-fold, indicating that the imidazole moiety of His-82 is a major determinant of catalytic rate enhancement by VatD. The structure of the VatD-dalfopristin complex can be used to predict positions where further structural modification of the drug might preclude enzyme binding and thereby circumvent Synercid resistance.

• Authors: Laura E Kehoe, Jaruwaree Snidwongse, Patrice Courvalin, John B Rafferty, Iain A Murray
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 278 Issue 32 Pg. 29963-70 (Aug 08 2003) ISSN: 0021-9258 [Print] United States
• PMID: 12771141 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• Ligands
• Virginiamycin
• quinupristin-dalfopristin
• Histidine
• Acetyltransferases
• virginiamycin acetyltransferase D
• Alanine
• dalfopristin

Topics

• Acetyltransferases (chemistry, genetics)
• Alanine (chemistry)
• Anti-Bacterial Agents (pharmacology)
• Binding Sites
• Catalysis
• Crystallography, X-Ray
• Drug Resistance
• Enterococcus faecium (pathogenicity)
• Gram-Positive Bacterial Infections (drug therapy)
• Histidine (chemistry)
• Ligands
• Models, Chemical
• Models, Molecular
• Mutagenesis, Site-Directed
• Protein Binding
• Protein Conformation
• Virginiamycin (analogs & derivatives, pharmacology)