1,2,4-Triazole-based first-in-class non-nucleoside inhibitors of bacterial enzyme MraY.

MraY, a bacterial enzyme crucial for the synthesis of peptidoglycans, represents a promising yet underexplored target for the development of effective antibacterial agents. Nature has provided several classes of nucleoside inhibitors of MraY and scientists have modified these structures further to obtain natural product-like inhibitors of MraY. The natural products and their synthetic analogs suffer from non-optimal in vivo efficacy, and the synthetic complexity of the structures renders the synthesis and structure-activity relationship (SAR) studies of these molecules particularly challenging. In this study, we present our findings on the discovery of first-in-class 1,2,4-triazole-based MraY inhibitors that are not nucleoside-derived. A series of 1,2,4-triazole analogous were identified by a structure-activity-relationship (SAR) study using a structure-based drug design strategy. Compound 1 , with an IC 50 of 171 µM against MraY from Staphylococcus aureus (MraY SA ), was optimized to compound 12a , exhibiting an IC 50 of 25 µM. Molecular docking studies against MraY SA provided insights into these compounds' binding interactions and activity. Furthermore, screening against the ESKAPE bacterial panel was also conducted, through which we discovered compounds demonstrating broad-spectrum antibacterial activity against E. faecium , methicillin-resistant S. aureus (MRSA), vancomycin-resistant Enterococci (VRE) strains and Mycobacterium tuberculosis . The novel, first-in-class non-nucleoside inhibitors of MraY highlighted in this work provide a strong proof-of-concept of how to leverage structural information of the protein to develop future antibacterial agents targeting MraY.