Hybrid inhibitors of DNA gyrase A and B

design, synthesis and evaluation

Martina Durcik (Avtor), Žiga Skok (Avtor), Janez Ilaš (Avtor), Nace Zidar (Avtor), Anamarija Zega (Avtor), Petra Éva Szili (Avtor), Tihomir Tomašić (Avtor), Gábor Draskovits (Avtor), Tamás Révész (Avtor), Danijel Kikelj (Avtor), Ákos Nyerges (Avtor), Csaba Pál (Avtor), Lucija Peterlin-Mašič (Avtor)

Povzetek

The discovery of multi-targeting ligands of bacterial enzymes is an important strategy to combat rapidly spreading antimicrobial resistance. Bacterial DNA gyrase and topoisomerase IV are validated targets for the development of antibiotics. They can be inhibited at their catalytic sites or at their ATP binding sites. Here we present the design of new hybrids between the catalytic inhibitor ciprofloxacin and ATP-competitive inhibitors that show low nanomolar inhibition of DNA gyrase and antibacterial activity against Gram-negative pathogens. The most potent hybrid 3a has MICs of 0.5 [micro]g/mL against Klebsiella pneumoniae, 4 [micro]g/mL against Enterobacter cloacae, and 2 [micro]g/mL against Escherichia coli. In addition, inhibition of mutant E. coli strains shows that these hybrid inhibitors interact with both subunits of DNA gyrase (GyrA, GyrB), and that binding to both of these sites contributes to their antibacterial activity.

Ključne besede

antibacterial;ciprofloxacin;DNA gyrase;dual inhibitor;hybrid;

Podatki

Jezik:	Angleški jezik
Leto izida:	2021
Tipologija:	1.01 - Izvirni znanstveni članek
Organizacija:	UL FFA - Fakulteta za farmacijo
UDK:	615.4:54:615.015.8
COBISS:	44007939
ISSN:	1999-4923
Št. ogledov:	200
Št. prenosov:	66
Ocena:	0 (0 glasov)
Metapodatki:

Ostali podatki

Sekundarni jezik:	Slovenski jezik
Sekundarne ključne besede:	DNK giraze;ciprofloksacin;zaviralci;hibridi;Bakterijska rezistenca;Farmacevtska kemija;
Vrsta dela (COBISS):	Članek v reviji
Strani:	str. 1-17
Letnik:	ǂVol. ǂ13
Zvezek:	ǂiss. ǂ1
Čas izdaje:	2021
DOI:	10.3390/pharmaceutics13010006
ID:	14418267