Improved N-phenylpyrrolamide inhibitors of DNA gyrase as antibacterial agents for high-priority bacterial strains
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<sub>50</sub> 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.
Authors
- Cristina D. Cruz (ORCID: https://orcid.org/0000-0003-4655-8563)
- Petra Szili (ORCID: https://orcid.org/0000-0002-4662-4260)
- Anamarija Zega (ORCID: https://orcid.org/0000-0003-4065-0019)
- Päivi Tammela (ORCID: https://orcid.org/0000-0003-4697-8066)
- Davide Benedetto Tiz (ORCID: https://orcid.org/0000-0002-2016-1210)
- Milija Jovanovic (ORCID: https://orcid.org/0000-0002-6004-8140)
- Márton Simon Czikkely (ORCID: https://orcid.org/0009-0008-6123-9927)
- Janez Ilaš (ORCID: https://orcid.org/0000-0002-0124-0474)
- Lucíja Peterlin Mašič (ORCID: https://orcid.org/0000-0003-0624-8472)
- Martina Durcik (ORCID: https://orcid.org/0000-0002-9218-1771)
- Tihomir Tomašič (ORCID: https://orcid.org/0000-0001-5534-209X)
- Csaba Pál (ORCID: https://orcid.org/0000-0002-5187-9903)
- Andrej Emanuel Cotman (ORCID: https://orcid.org/0000-0003-2528-396X)
- Alessia Onali
- Lidija Šenerović (ORCID: https://orcid.org/0000-0002-6965-9407)
- Jaka Dernovšek (ORCID: https://orcid.org/0000-0003-3370-8163)
- Nace Zidar (ORCID: https://orcid.org/0000-0003-1905-0158)
- Žiga Skok (ORCID: https://orcid.org/0000-0002-3150-360X)
- D. Kikelj (ORCID: https://orcid.org/0000-0002-2067-7604)
- Martina Hrast Rambaher
- Peter Peršolja
Institutions
- University of Helsinki (FI)
- University of Ljubljana (SI)
- University of Szeged (HU)
- HUN-REN Szegedi Biológiai Kutatóközpont (HU)
- University of Belgrade (RS)
- Institute of Biochemistry (HU)
- Hungarian Academy of Sciences (HU)
Publication Details
- Journal
- European Journal of Medicinal Chemistry
- Published
- 2024-09-01
- DOI
- https://doi.org/10.1016/j.ejmech.2024.116823
- Citations
- 3
- Primary Topic
- Cancer therapeutics and mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.70
Funders
- Academy of Finland
- Javna Agencija za Raziskovalno Dejavnost RS