Inhibition of MurA enzyme from Escherichia coli and Staphy-lococcus aureus by diterpenes from Lepechinia meyenii and their synthetic analogs

Abstract

Enzymes MurA and MurF, involved in bacterial cell wall synthesis, have been validatedas targets for the discovery of novel antibiotics. A panel of plant-origin antibacterial diterpenesand synthetic analogs derived therefrom were investigated for their inhibitory properties on theseenzymes from Escherichia coli and Staphylococcus aureus. Six compounds were proven to be effectivefor inhibiting MurA from both bacteria, with IC50 values ranging from 1.1 to 25.1 M. To furthermechanistically investigate the nature of binding and to explain the activity, these compounds weredocked into the active site of MurA from E. coli. The aromatic ring of the active compounds showeda T-shaped ? interaction with the phenyl ring of Phe328, and at least one hydrogen bond wasformed between the hydroxy groups and Arg120 and/or Arg91. The results disclosed here establishnew chemical scaffolds for the development of novel entities targeting MurA as potential antibioticsto combat the threat of pathogenic bacteria, particularly resistant strains.