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

Sergio C. Chai, Wen Long Wang, De Rong Ding, Qi Zhuang Ye

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3537-3540
Number of pages4
JournalEuropean Journal of Medicinal Chemistry
Volume46
Issue number8
DOIs
StatePublished - Aug 1 2011

Keywords

  • Antibiotic
  • Drug discovery
  • Drug resistance
  • Enzyme inhibition
  • Hydrolase
  • Metalloenzyme

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

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