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

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...

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Autores principales: Durcik, Martina, Skok, Žiga, Ilaš, Janez, Zidar, Nace, Zega, Anamarija, Szili, Petra Éva, Draskovits, Gábor, Révész, Tamás, Kikelj, Danijel, Nyerges, Akos, Pál, Csaba, Mašič, Lucija Peterlin, Tomašič, Tihomir
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822030/
https://www.ncbi.nlm.nih.gov/pubmed/33374964
http://dx.doi.org/10.3390/pharmaceutics13010006
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author Durcik, Martina
Skok, Žiga
Ilaš, Janez
Zidar, Nace
Zega, Anamarija
Szili, Petra Éva
Draskovits, Gábor
Révész, Tamás
Kikelj, Danijel
Nyerges, Akos
Pál, Csaba
Mašič, Lucija Peterlin
Tomašič, Tihomir
author_facet Durcik, Martina
Skok, Žiga
Ilaš, Janez
Zidar, Nace
Zega, Anamarija
Szili, Petra Éva
Draskovits, Gábor
Révész, Tamás
Kikelj, Danijel
Nyerges, Akos
Pál, Csaba
Mašič, Lucija Peterlin
Tomašič, Tihomir
author_sort Durcik, Martina
collection PubMed
description 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.
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spelling pubmed-78220302021-01-23 Hybrid Inhibitors of DNA Gyrase A and B: Design, Synthesis and Evaluation Durcik, Martina Skok, Žiga Ilaš, Janez Zidar, Nace Zega, Anamarija Szili, Petra Éva Draskovits, Gábor Révész, Tamás Kikelj, Danijel Nyerges, Akos Pál, Csaba Mašič, Lucija Peterlin Tomašič, Tihomir Pharmaceutics Article 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. MDPI 2020-12-22 /pmc/articles/PMC7822030/ /pubmed/33374964 http://dx.doi.org/10.3390/pharmaceutics13010006 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Durcik, Martina
Skok, Žiga
Ilaš, Janez
Zidar, Nace
Zega, Anamarija
Szili, Petra Éva
Draskovits, Gábor
Révész, Tamás
Kikelj, Danijel
Nyerges, Akos
Pál, Csaba
Mašič, Lucija Peterlin
Tomašič, Tihomir
Hybrid Inhibitors of DNA Gyrase A and B: Design, Synthesis and Evaluation
title Hybrid Inhibitors of DNA Gyrase A and B: Design, Synthesis and Evaluation
title_full Hybrid Inhibitors of DNA Gyrase A and B: Design, Synthesis and Evaluation
title_fullStr Hybrid Inhibitors of DNA Gyrase A and B: Design, Synthesis and Evaluation
title_full_unstemmed Hybrid Inhibitors of DNA Gyrase A and B: Design, Synthesis and Evaluation
title_short Hybrid Inhibitors of DNA Gyrase A and B: Design, Synthesis and Evaluation
title_sort hybrid inhibitors of dna gyrase a and b: design, synthesis and evaluation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822030/
https://www.ncbi.nlm.nih.gov/pubmed/33374964
http://dx.doi.org/10.3390/pharmaceutics13010006
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