Abstract
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.
Highlights
We use mass spectrometry analysis and molecular modelling to show the established antimicrobial inhibitor 4,5-dichloro-1,2dithiol-3-one (HR45) acts by forming a covalent adduct with the target β-ketoacyl-acyl carrier protein (ACP) synthase III (FabH)
Most bacteria utilise a complex of proteins termed type II fatty acid synthase (FAS II), whereby each functionality is carried out by a discreet enzyme, between which the growing acyl chain is transported by the acyl carrier protein (ACP).[1]
We have shown that the 1,2-dithiol-3-one HR45 covalently modifies saFabH through a Michael-type addition elimination at the catalytic residue C112
Summary
We use mass spectrometry analysis and molecular modelling to show the established antimicrobial inhibitor 4,5-dichloro-1,2dithiol-3-one (HR45) acts by forming a covalent adduct with the target β-ketoacyl-ACP synthase III (FabH). Subsequent structure–activity relationship studies showed that the chlorine in the 5-position was found to be essential for irreversible inhibition of FabH isoforms from both Staphylococcus aureus (saFabH) and Escherichia coli (ecFabH) with reported IC50 values of 156 nM and 2.0 μM, respectively.[15] The reported mode of inhibition was inconclusive, and despite postulating covalent modification via a Michael-type mechanism they were unable to obtain data to support this hypothesis.
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