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

Abstract

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 has never been exploited. Inside the cytoplasm a group of enzyme known as Mur enzymes having similar mechanism of action using ATP, act consecutively and the active residues for all the enzymes are conserved. These make them ideal for multi-target. The MurD involve in adding the D-glu amino acid whereas MurE involve for L-Lys/m-DAP amino acid addition. The MurE act as a gatekeeper for gram-positive and gram-negative bacteria. The product of the previous enzyme act as a substrate for the next one. By designing similar chemical nature to the MurD product, will be having the dual affinity. But the major drawback of these inhibitors are penetration. The IC 50 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 scaffold using various drug designing tools to get the desired hits. The MIC values and time kill studies of the synthesized compound has been carried out against MRSA (ATCC-43300). All the MICs were within µg/ml and better time-kill studies shown against the standard drug ciprofloxacin. These hits can optimized further to get the desired lead.