Growth inhibition of Escherichia coli and methicillin-resistant Staphylococcus aureus by targeting cellular methionine aminopeptidase

Methionine aminopeptidase (MetAP) catalyzes the N-terminal methionine excision from the majority of newly synthesized proteins, which is an essential cotranslational process required for cell survival. As such, MetAP has become an appealing target for the development of antimicrobial therapeutics with novel mechanisms of action. By screening a library of small organic molecules, we previously discovered a class of compounds that selectively inhibit the Fe(II)-form of MetAP. Herein, we demonstrate that some of these compounds and their newly synthesized derivatives halt the growth of Escherichia coli and Staphylococcus aureus cells with significant potency. The most potent compound inhibited methicillin-resistant S. aureus (MRSA) growth with an IC50 value of 1 μM and MIC of 0.7 μg/ml. Two cell-based assays were used to verify that MetAP is the intracellular target in E. coli cells. These findings can serve as foundation for the development of novel therapeutics against an ever increasing threat by drug resistant staphylococcal infections.

Antibacterial methionine aminopetidase inhibitorsFigure optionsDownload as PowerPoint slideHighlights
► Inhibitors of methionine aminopeptidase displayed antibacterial activity.
► Growth of drug-susceptible and methicillin-resistant S. aureus was inhibited.
► Cell-based assays validate methionine aminopeptidase as the intracellular target.