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This study presents the discovery of a new series of N -phenylpyrrolamide inhibitors of bacterial DNA gyrase with improved antibacterial activity. The most potent inhibitors had low nanomolar IC 50 values against Escherichia coli DNA gyrase (IC 50 ; 2-20 nM) and E. coli topoisomerase IV (22i, IC 50 = 143 nM). Importantly, none of the compounds showed activity against human DNA topoisomerase IIα, indicating selectivity for bacterial targets. Among the tested compounds, 22e emerged as the most effective against Gram-positive bacteria with minimum inhibitory concentration (MIC) values of 0.25 μg mL -1 against Staphylococcus aureus ATCC 29213 and MRSA, and 0.125 μg mL -1 against Enterococcus faecalis ATCC 29212. For Gram-negative bacteria, compounds 23b and 23c showed the greatest efficacy with MIC values ranging from 4 to 32 μg mL -1 against E. coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Acinetobacter baumannii ATCC 17978 and A. baumannii ATCC 19606. Notably, compound 23b showed promising activity against the clinically relevant Gram-negative pathogen Klebsiella pneumoniae ATCC 10031, with an MIC of 0.0625 μg mL -1 . Furthermore, compounds 23a and 23c exhibited significantly lower susceptibility to resistance development compared to novobiocin in S. aureus ATCC 29213 and K. pneumoniae ATCC 10031. Overall, the most promising compounds of this series showed excellent on-target potency, marking a significant improvement over previous N -phenylpyrrolamide inhibitors., Competing Interests: The authors declare no competing financial interest., (This journal is © The Royal Society of Chemistry.)