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

Zidar, Nace (author), Onali, Alessia (author), Peršolja, Peter (author), Benedetto Tiz, Davide (author), Dernovšek, Jaka (author), Skok, Žiga (author), Durcik, Martina (author), Cotman, Andrej Emanuel (author), Hrast, Martina (author), Zega, Anamarija (author), Peterlin-Mašič, Lucija (author), Ilaš, Janez (author), Tomašič, Tihomir (author), Kikelj, Danijel (author)

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 IC$_{50}$ 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.

• Language: English
• Keywords: antibacterial agents, DNA gyrase, GyrB, inhibitor, N-phenylpyrrolamide, ParE, topoisomerase IV
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2024
• Number of pages: 19 str.
• Numbering: Vol. 278, art. 116823
• PID: 20.500.12556/RUL-161296-97649312-2105-afd9-1e19-84dcee14eee0
• UDC: 615.4:54
• ISSN on article: 1768-3254
• DOI: 10.1016/j.ejmech.2024.116823
• COBISS.SI-ID: 206357251
• Publication date in RUL: 09.09.2024

Record is a part of a journal

• Title: European journal of medicinal chemistry
• Shortened title: Eur. j. med. chem.
• Publisher: Elsevier
• ISSN: 1768-3254
• COBISS.SI-ID: 23138309

Licences

• License: CC BY-NC 4.0, Creative Commons Attribution-NonCommercial 4.0 International
• Link: http://creativecommons.org/licenses/by-nc/4.0/
• Description: A creative commons license that bans commercial use, but the users don’t have to license their derivative works on the same terms.

Secondary language

• Language: Slovenian
• Keywords: antibakterijski zaviralci, DNA giraze, GyrB, N-fenilpirolamid, ParE, topoizomeraza IV, farmacevtska kemija