The alarming multiple drug resistance developed by Escherichia coli towards the routine conventional antibiotics owing to their non-judicious usage is fast becoming a tough menace. This necessitates the urgent unleashing of novel and diverse strategies and antibacterial compounds. Since finding a new antibiotic from the scratch, followed by endless clinical trials is exceedingly time-consuming, a powerful alternate strategy of CADD coupled with repurposing the available drugs could save precious time and money. DNA gyrases (topoisomerase II) of E.coli are among the promising new drug targets. The interface between the N-terminal domain of gyrA and C- terminal domain of gyrB which is targeted by most of the available inhibitory drugs, is of particular interest. Crucial active site residues within the N-terminal domain of gyrA were delineated through a literature search. FDA approved drugs were docked using FlexX on the receptors created around the co-crystallized reference ligand. Based on the docking scores and interactions with crucial residues, 12 leads were shortlisted, namely ceforanide, tetrahydrofolic acid, azlocillin, cefazolin, adenosine triphosphate, cefixime, dihydronicotinamide adenine dinucleotide, moxalactam, leucal, cromoglicic acid, cefotetan, and cedax. Surprisingly quinolones, which are approved inhibitors of gyrases were not picked up in the top leads, rather, the most dominant class of molecules that docked successfully was cephalosporin. Our results indicated that these cephalosporins, as well as the other shortlisted leads, could be further optimized and validated through in-vitro experiments for their potential as gyraseA antagonists. Hence the present study holds immense promise in combating MDR of human bacterial pathogens.