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  3. Improved N-phenylpyrrolamide inhibitors of DNA gyrase as antibacterial agents for high-priority bacterial strains

Improved N-phenylpyrrolamide inhibitors of DNA gyrase as antibacterial agents for high-priority bacterial strains

  • Eur J Med Chem. 2024 Nov 15:278:116823. doi: 10.1016/j.ejmech.2024.116823.
Nace Zidar 1,  Alessia Onali 2,  Peter Peršolja 2,  Davide Benedetto Tiz 2,  Jaka Dernovšek 2,  Žiga Skok 2,  Martina Durcik 2,  Andrej Emanuel Cotman 2,  Martina Hrast Rambaher 2,  Cristina D Cruz 3,  Päivi Tammela 3,  Lidija Senerovic 4,  Milija Jovanovic 4,  Petra Éva Szili 5,  Márton Simon Czikkely 6,  Csaba Pál 5,  Anamarija Zega 2,  Lucija Peterlin Mašič 2,  Janez Ilaš 2,  Tihomir Tomašič 2,  Danijel Kikelj 2
Affiliations

Affiliations

  • 1 University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000, Ljubljana, Slovenia. Electronic address: nace.zidar@ffa.uni-lj.si.
  • 2 University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000, Ljubljana, Slovenia.
  • 3 Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, Viikinkaari 5E, Helsinki, 00014, Finland.
  • 4 Laboratory for Microbial Molecular Genetics and Ecology, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11 042, Belgrade, Serbia.
  • 5 Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, H-6726, Hungary.
  • 6 Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, H-6726, Hungary; Doctoral School of Multidisciplinary Medical Sciences, University of Szeged, Szeged, HU-6722, Hungary; Department of Forensic Medicine, Albert-Szent-Györgyi Medical School, University of Szeged, Szeged, HU-6722, Hungary.
PMID: 39236496 DOI: 10.1016/j.ejmech.2024.116823
Abstract

In this work, we describe an improved series of N-phenylpyrrolamide inhibitors that exhibit potent activity against DNA gyrase and are highly effective against high-priority gram-positive bacteria. The most potent compounds show low nanomolar IC50 values against Escherichia coli DNA gyrase, and in addition, compound 7c also inhibits E. coli Topoisomerase IV in the nanomolar concentration range, making it a promising candidate for the development of potent dual inhibitors for these Enzymes. All tested compounds show high selectivity towards the human isoform DNA Topoisomerase IIα. Compounds 6a, 6d, 6e and 6f show MIC values between 0.031 and 0.0625 μg/mL against vancomycin-intermediate S. aureus (VISA) and Enterococcus faecalis strains. Compound 6g shows an inhibitory effect against the methicillin-resistant S. aureus strain (MRSA) with a MIC of 0.0625 μg/mL and against the E. faecalis strain with a MIC of 0.125 μg/mL. In a time-kill assay, compound 6d showed a dose-dependent bactericidal effect on the MRSA strain and achieved bactericidal activity at 8 × MIC after 8 h. The duration of the post-antibiotic effect (PAE) on the MRSA strain for compound 6d was 2 h, which corresponds to the PAE duration for ciprofloxacin. The compounds were not cytotoxic at effective concentrations, as determined in an MTS assay on the MCF-7 breast Cancer cell line.

Keywords

Antibacterial; DNA gyrase; GyrB; Inhibitor; N-phenylpyrrolamide; ParE; Topoisomerase IV.

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