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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...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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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. |
format | Online Article Text |
id | pubmed-7822030 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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