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

Peter J. Stogios, Misty L. Kuhn, Elena Evdokimova, Patrice Courvalin, Wayne F. Anderson, Alexei Savchenko*

*Corresponding author for this work

Research output: Contribution to journalArticle

6 Scopus citations

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 vancomycinresistant 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.

Original languageEnglish (US)
Pages (from-to)7083-7092
Number of pages10
JournalAntimicrobial agents and chemotherapy
Volume58
Issue number12
DOIs
StatePublished - Dec 1 2014

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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