Ekström, Alex; Kelly, Van; Marles-Wright, Jon; Cockroft, Scott; Campopiano, Dominic. (2017). Structural evidence for the covalent modification of FabH by 4,5-dichloro-1,2-dithiol-3-one (HR45), [dataset]. University of Edinburgh. School of Chemistry. http://dx.doi.org/10.7488/ds/2103.
We use mass spectrometry analysis and molecular modelling to show the established antimicrobial inhibitor 4,5-dichloro-1,2-dithiol-3-one (HR45) acts by forming a covalent adduct with the target β-ketoacyl-ACP synthase III (FabH). The 5-chloro substituent directs attack of the essential active site thiol (C112) via a Michael-type addition elimination reaction mechanism.