title: Growth inhibition of Escherichia coli and methicillin-resistant Staphylococcus aureus by targeting cellular methionine aminopeptidase.
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 IC(50) 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202, USA.
authors.forename: Sergio C
authors.initials: SC
authors.lastname: Chai
authors.forename: Wen-Long
authors.initials: WL
authors.lastname: Wang
authors.forename: De-Rong
authors.initials: DR
authors.lastname: Ding
authors.forename: Qi-Zhuang
authors.initials: QZ
authors.lastname: Ye
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects*; D002645:Chickens; D003374:Coumarins / Q000032:analysis; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000382:microbiology; D005456:Fluorescent Dyes / Q000032:analysis; D006801:Humans; D020128:Inhibitory Concentration 50; D013058:Mass Spectrometry; D016106:Methicillin Resistance / Q000187:drug effects; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology; D063208:Methionyl Aminopeptidases; D008826:Microbial Sensitivity Tests; D010957:Plasmids; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: D000900:Anti-Bacterial Agents; D003374:Coumarins; D005456:Fluorescent Dyes; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D054852:Small Molecule Libraries; D000626:Aminopeptidases; D063208:Methionyl Aminopeptidases