Dual Inhibition of MurD and MurE: A strategy for the development of antibacterial agents against methicillin resistant Staphylococcus aureus

Bacterial resistance is one of the biggest threat to health community, especially hospital acquired MRSA. There are various mechanisms are involved in bacterial resistance out of which, the penetration of cell wall and the mutation of target receptor are the most important. From the beginning, the later stage of Peptidoglycan synthesis has been targeted which occurs outside the cytoplasm. The early stage of peptidoglycan synthesis is not well exploited. ATP dependent bacterial Mur enzymes have similar topology and mechanism of action and act consecutively. Active site residues for all these enzymes are conserved. These make them ideal for development of multi-target antibacterial agents. The MurD add D-glutamine whereas MurE adds L-Lys/m-DAP amino acid. The MurE act as a gatekeeper for both Gram-positive and Gram-negative bacteria. The products of the previous enzyme act as a substrate for the next one. By designing similar chemical nature to the MurD product, compound will have the dual affinity. But the major drawback of these inhibitors is penetration of bacterial cell wall. The IC₅₀ values and the MIC values have not correlated for most of the inhibitors. The current work is focused on this problem and we have designed some novel scaffolds using multiple computational approaches. Compounds were synthesized by conventional method and characterized. The MIC values and time kill studies of the synthesized compound has been carried out against MRSA (ATCC-43300). Some of the compounds showed potent activity and bactericidal activity in time –kill studies. Results are compared with standard drug ciprofloxacin.