Hypersusceptibility of Human Cytomegalovirus to Foscarnet Induced by Mutations in Helices K and P of the Viral DNA Polymerase

Antimicrob Agents Chemother. 2020 Mar 24;64(4):e01910-19. doi: 10.1128/AAC.01910-19. Print 2020 Mar 24.

Abstract

Herein, we phenotypically and enzymatically characterize the theoretical mutation Q579I in helix K and the already described clinical mutation K805Q in helix P of cytomegalovirus DNA polymerase for susceptibility to foscarnet. Q579I and K805Q recombinant viruses were hypersusceptible to foscarnet (respective mean 50% effective concentrations [EC50] of 0.12- and 0.19-fold that of the wild type). Three-dimensional modeling analysis suggested that both mutations favor the closed conformation of the enzyme to which foscarnet binds with a higher affinity.

Keywords: DNA polymerase; foscarnet; human cytomegalovirus; hypersusceptibility; molecular modeling; resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / pharmacology*
  • Cytomegalovirus / drug effects*
  • Cytomegalovirus / genetics*
  • Cytomegalovirus Infections / drug therapy
  • DNA, Viral / genetics
  • DNA-Directed DNA Polymerase / drug effects
  • DNA-Directed DNA Polymerase / genetics*
  • Drug Resistance, Viral / genetics
  • Foscarnet / pharmacology*
  • Humans
  • Models, Molecular
  • Mutation

Substances

  • Antiviral Agents
  • DNA, Viral
  • Foscarnet
  • DNA-Directed DNA Polymerase

Grants and funding