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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| Main Authors: | , , , , , , , , , , , , |
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| Format: | Book |
| Published: |
MDPI AG,
2020-12-01T00:00:00Z.
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| Online Access: | Connect to this object online. |
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| Summary: | 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 <b>3a</b> has MICs of 0.5 µg/mL against <i>Klebsiella pneumoniae</i>, 4 µg/mL against <i>Enterobacter cloacae</i>, and 2 µg/mL against <i>Escherichia coli</i>. In addition, inhibition of mutant <i>E. coli</i> 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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| Item Description: | 10.3390/pharmaceutics13010006 1999-4923 |