The identification of inhibitory compounds of Rickettsia prowazekii methionine aminopeptidase for antibacterial applications

Abstract Methionine aminopeptidase (MetAP) is a dinuclear metalloprotease responsible for the cleavage of methionine initiator residues from nascent proteins. MetAP activity is necessary for bacterial proliferation and is therefore a projected novel antibacterial target. A compound library consisting of 294 members containing metal-binding functional groups was screened against Rickettsia prowazekii MetAP to determine potential inhibitory motifs. The compounds were first screened against the target at a concentration of 10 µM and potential hits were determined to be those exhibiting greater than 50% inhibition of enzymatic activity. These hit compounds were then rescreened against the target in 8-point dose–response curves and 11 compounds were found to inhibit enzymatic activity with IC 50 values of less than 10 µM. Finally, compounds ( 1–5 ) were docked against Rp MetAP with AutoDock to determine potential binding mechanisms and the results were compared with crystal structures deposited within the PDB.