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

Povzetek

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.

Ključne besede

antibacterial;DNA gyrase;GyrB;inhibitor;N-phenylpyrrolamide;ParE;topoisomerase IV;

Podatki

Jezik: Angleški jezik
Leto izida:
Tipologija: 1.01 - Izvirni znanstveni članek
Organizacija: UL FFA - Fakulteta za farmacijo
UDK: 615.4:54
COBISS: 206357251 Povezava se bo odprla v novem oknu
ISSN: 1768-3254
Št. ogledov: 45
Št. prenosov: 31
Ocena: 0 (0 glasov)
Metapodatki: JSON JSON-RDF JSON-LD TURTLE N-TRIPLES XML RDFA MICRODATA DC-XML DC-RDF RDF

Ostali podatki

Sekundarni jezik: Slovenski jezik
Sekundarne ključne besede: antibakterijski zaviralci;DNA giraze;GyrB;N-fenilpirolamid;ParE;topoizomeraza IV;Farmacevtska kemija;
Vrsta dela (COBISS): Članek v reviji
Strani: 19 str.
Zvezek: ǂVol. ǂ278
Čas izdaje: 2024
DOI: 10.1016/j.ejmech.2024.116823
ID: 24985084