New N-phenylpyrrolamide inhibitors of DNA gyrase with improved antibacterial activity

Cotman, Andrej Emanuel and Fulgheri, Federica and Piga, Martina and Persolja, Peter and Tiz, Davide Benedetto and Skok, Ziga and Durcik, Martina and Sterle, Masa and Dernovsek, Jaka and Cruz, Cristina D. and Tammela, Paivi and Szili, Petra and Daruka, Lejla and Pál, Csaba and Zega, Anamarija and Masic, Lucija Peterlin and Ilas, Janez and Tomasic, Tihomir and Kikelj, Danijel and Zidar, Nace (2024) New N-phenylpyrrolamide inhibitors of DNA gyrase with improved antibacterial activity. RSC ADVANCES, 14 (39). pp. 28423-28454. ISSN 2046-2069

Preview

Text CotmanA_NewN-phenylpyrrolamide.pdf Available under License Creative Commons Attribution Non-commercial. Download (1MB) | Preview

Abstract

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 IC50 values against Escherichia coli DNA gyrase (IC50; 2–20 nM) and E. coli topoisomerase IV (22i, IC50 = 143 nM). Importantly, none of the compounds showed activity against human DNA topoisomerase IIa, 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 mg mL−1 against Staphylococcus aureus ATCC 29213 and MRSA, and 0.125 mg 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 mg 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 mg 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.

Actions (login required)

Edit Item