MraY Inhibitors Research Articles

Synthesis of the Nucleoside Moiety of Liposidomycins: Elucidation of the Pharmacophore of this Family of MraY Inhibitors

Tunicamycins (TCMs) and liposidomycins (LPMs) are naturally occurring inhibitors of the bacterial translocase (MraY). Based on structure–activity relationship (SAR) studies, a molecular model has been proposed for their inhibitory mechanism. This study points out the importance of the nucleoside moiety of liposidomycins in the inhibition of MraY. A simplified molecule ( I) based on the liposidomycin core structure has been synthesised and tested on MraY. The compound displayed a moderate inhibitory activity (IC 50=50 μM). The validation of the molecular model was then performed by synthesising higher homologues of I, containing an additional stereocentre in the 5′ position ( XIV and XV). In agreement with the prediction, only the ( S) isomer XV showed significant activity against MraY (IC 50= 5 μM).

Assay for Identification of Inhibitors for Bacterial MraY Translocase or MurG Transferase

Bacterial peptidoglycan synthesis is a well-characterized system for targeting new antimicrobial drugs. Formation of the peptidoglycan precursors Lipid I and Lipid II is catalyzed by the gene products of mraY and murG, which are involved in the first and second steps of the lipid cycle reactions, respectively. Here we describe the development of an assay specific for identifying inhibitors of MraY or MurG, based on the detection of radiolabeled [14C]GlcNAc incorporated into Lipid II. Assay specificity is achieved with the biotin tagging of the Lipid I precursor UDP-MurNAc-pentapeptide. This allows for the separation and identification of lipid products produced by the enzymatic activity of the MraY and MurG proteins, and thus identification of specific inhibitors.