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Hybrid Inhibitors of DNA Gyrase A and B: Design, Synthesis and Evaluation

Authors :
Martina Durcik
Žiga Skok
Janez Ilaš
Nace Zidar
Anamarija Zega
Petra Éva Szili
Gábor Draskovits
Tamás Révész
Danijel Kikelj
Akos Nyerges
Csaba Pál
Lucija Peterlin Mašič
Tihomir Tomašič
Source :
Pharmaceutics, Vol 13, Iss 1, p 6 (2020)
Publication Year :
2020
Publisher :
MDPI AG, 2020.

Abstract

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 µg/mL against Klebsiella pneumoniae, 4 µg/mL against Enterobacter cloacae, and 2 µg/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.

Details

Language :
English
ISSN :
19994923
Volume :
13
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Pharmaceutics
Publication Type :
Academic Journal
Accession number :
edsdoj.b21ef8c08f5f42f5bcc65fa01c759cd9
Document Type :
article
Full Text :
https://doi.org/10.3390/pharmaceutics13010006