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Potential for reduction of streptogramin A resistance revealed by structural analysis of acetyltransferase VatA.

Abstract
Combinations of group A and B streptogramins (i.e., dalfopristin and quinupristin) are "last-resort" antibiotics for the treatment of infections caused by Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. Resistance to streptogramins has arisen via multiple mechanisms, including the deactivation of the group A component by the large family of virginiamycin O-acetyltransferase (Vat) enzymes. Despite the structural elucidation performed for the VatD acetyltransferase, which provided a general molecular framework for activity, a detailed characterization of the essential catalytic and antibiotic substrate-binding determinants in Vat enzymes is still lacking. We have determined the crystal structure of S. aureus VatA in apo, virginiamycin M1- and acetyl-coenzyme A (CoA)-bound forms and provide an extensive mutagenesis and functional analysis of the structural determinants required for catalysis and streptogramin A recognition. Based on an updated genomic survey across the Vat enzyme family, we identified key conserved residues critical for VatA activity that are not part of the O-acetylation catalytic apparatus. Exploiting such constraints of the Vat active site may lead to the development of streptogramin A compounds that evade inactivation by Vat enzymes while retaining binding to their ribosomal target.
AuthorsPeter J Stogios, Misty L Kuhn, Elena Evdokimova, Patrice Courvalin, Wayne F Anderson, Alexei Savchenko
JournalAntimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 58 Issue 12 Pg. 7083-92 (Dec 2014) ISSN: 1098-6596 [Electronic] United States
PMID25223995 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
CopyrightCopyright © 2014, American Society for Microbiology. All Rights Reserved.
Chemical References
  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Recombinant Proteins
  • Acetyl Coenzyme A
  • Streptogramin A
  • Acetyltransferases
Topics
  • Acetyl Coenzyme A (chemistry)
  • Acetyltransferases (antagonists & inhibitors, chemistry, genetics)
  • Amino Acid Sequence
  • Anti-Bacterial Agents (chemistry)
  • Bacterial Proteins (antagonists & inhibitors, chemistry, genetics)
  • Catalytic Domain
  • Crystallography, X-Ray
  • Drug Resistance, Bacterial (genetics)
  • Gene Expression
  • Gram-Negative Bacteria (chemistry, enzymology)
  • Gram-Positive Bacteria (chemistry, enzymology)
  • Models, Molecular
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Protein Binding
  • Recombinant Proteins (chemistry, genetics)
  • Sequence Alignment
  • Streptogramin A (chemistry)

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