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The present study is conducted to find the solution of rising antimicrobial resistance (AMR) in Escherichia coli which is a pathogen responsible for fatal systemic infections in human and animals. The enzyme dihydrofolate reductase (DHFR) is found in all organisms. In this study DHFR of E. coli (ec-DHFR) and human DHFR (h-DHFR) is targeted by novel chemical entities (NCE) from the Pathogen box of Medicines for Malaria Venture, Switzerland (MMV) using molecular modelling. The in-silico studies were further validated by in-vitro assays. The virtual screening of 400 MMV compounds was conducted using PyRx standard tool followed by manual docking of selected compounds by Autodock vina and Ligplot program. The in-silico studies showed good binding energy and strong hydrogen bond in docking of MMV675968 with ec-DHFR and no hydrogen bond with h-DHFR. This was further validated by the Molecular dynamic studies that revealed high binding free energy in ec-DHFR and in-vitro assays that produced good synergy in combination study of MMV675968 with last line (meropenem) and last resort (colistin) antibiotics. The extensive MD simulation and energetic analysis thus concludes that MMV675968 targets ec-DHFR. The combination studies were conducted with MMV675968 and FDA approved drugs against a panel of multidrug resistant Escherichia coli isolates. The synergistic results obtained in combination studies concluded that in-vitro data is consistent with in-silico data and that MMV675968 is a potential lead for future process of antimicrobial drug development against the multidrug resistance E. coli .Communicated by Ramaswamy H. Sarma.