Structurally Optimized Potent Dual-Targeting NBTI Antibacterials with an Enhanced Bifurcated Halogen-Bonding Propensity
© 2021 The Authors. Published by American Chemical Society..
We designed and synthesized an optimized library of novel bacterial topoisomerase inhibitors with p-halogenated phenyl right-hand side fragments and significantly enhanced and balanced dual-targeted DNA gyrase and topoisomerase IV activities of Staphylococcus aureus and Escherichia coli. By increasing the electron-withdrawing properties of the p-halogenated phenyl right-hand side fragment and maintaining a similar lipophilicity and size, an increased potency was achieved, indicating that the antibacterial activities of this series of novel bacterial topoisomerase inhibitors against all target enzymes are determined by halogen-bonding rather than van der Waals interactions. They show nanomolar enzyme inhibitory and whole-cell antibacterial activities against S. aureus and methicillin-resistant S. aureus (MRSA) strains. However, due to the relatively high substrate specificity for the bacterial efflux pumps, they tend to be less potent against E. coli and other Gram-negative pathogens.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:12 |
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| Enthalten in: |
ACS medicinal chemistry letters - 12(2021), 9 vom: 09. Sept., Seite 1478-1485 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kokot, Maja [VerfasserIn] |
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| Anmerkungen: |
Date Revised 17.09.2021 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1021/acsmedchemlett.1c00345 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM330691732 |
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| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a © 2021 The Authors. Published by American Chemical Society. | ||
| 520 | |a We designed and synthesized an optimized library of novel bacterial topoisomerase inhibitors with p-halogenated phenyl right-hand side fragments and significantly enhanced and balanced dual-targeted DNA gyrase and topoisomerase IV activities of Staphylococcus aureus and Escherichia coli. By increasing the electron-withdrawing properties of the p-halogenated phenyl right-hand side fragment and maintaining a similar lipophilicity and size, an increased potency was achieved, indicating that the antibacterial activities of this series of novel bacterial topoisomerase inhibitors against all target enzymes are determined by halogen-bonding rather than van der Waals interactions. They show nanomolar enzyme inhibitory and whole-cell antibacterial activities against S. aureus and methicillin-resistant S. aureus (MRSA) strains. However, due to the relatively high substrate specificity for the bacterial efflux pumps, they tend to be less potent against E. coli and other Gram-negative pathogens | ||
| 650 | 4 | |a Journal Article | |
| 700 | 1 | |a Weiss, Matjaž |e verfasserin |4 aut | |
| 700 | 1 | |a Zdovc, Irena |e verfasserin |4 aut | |
| 700 | 1 | |a Hrast, Martina |e verfasserin |4 aut | |
| 700 | 1 | |a Anderluh, Marko |e verfasserin |4 aut | |
| 700 | 1 | |a Minovski, Nikola |e verfasserin |4 aut | |
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