Mechanistic analysis of muraymycin analogues: a guide to the design of MraY inhibitors.

The systematic structure-activity relationship (SAR) of the muraymycins (MRYs) using an Ugi four-component reaction (U4CR) was investigated. The impact of the lipophilic substituent on antibacterial activity was significant, and the analogues 8 and 9 having a lipophilic side chain exhibited good activity against a range of Gram-positive bacterial pathogens, including MRSA and VRE. Further investigation of compounds 8 and 9 revealed these analogues to be selective inhibitors of the MraY transferase and nontoxic to HepG2 cells. The SAR of the accessory urea-peptide moiety indicated that it could be simplified. Our SAR study of the MRYs suggests a probable mechanism for inhibition of the MraY, where the inner moiety of the urea-dipeptide motif interacts with the carbohydrate recognition domain in the cytoplasmic loop 5. The predicted binding model would provide further direction toward the design of potent MraY inhibitors. This study has set the stage for the generation of novel antibacterial "lead" compounds based on MRYs.