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Structurally optimized potent dual-targeting NBTI antibacterials with an enhanced bifurcated halogen-bonding propensity
ID Kokot, Maja (Author), ID Weiss, Matjaž (Author), ID Zdovc, Irena (Author), ID Hrast, Martina (Author), ID Anderluh, Marko (Author), ID Minovski, Nikola (Author)

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Abstract
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.

Language:English
Keywords:NBTIs, DNA gyrase, topoisomerase IV, bifurcated halogen bonds, dual targeting
Work type:Article
Typology:1.01 - Original Scientific Article
Organization:FFA - Faculty of Pharmacy
Publication status:Published
Publication version:Version of Record
Year:2021
Number of pages:Str. 1478-1485
Numbering:Vol. 12, iss. 9
PID:20.500.12556/RUL-141453 This link opens in a new window
UDC:615.4:54:579
ISSN on article:1948-5875
DOI:10.1021/acsmedchemlett.1c00345 This link opens in a new window
COBISS.SI-ID:73185027 This link opens in a new window
Publication date in RUL:29.09.2022
Views:359
Downloads:42
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Record is a part of a journal

Title:ACS medicinal chemistry letters
Publisher:American Chemical Society
ISSN:1948-5875
COBISS.SI-ID:2959217 This link opens in a new window

Licences

License:CC BY 4.0, Creative Commons Attribution 4.0 International
Link:http://creativecommons.org/licenses/by/4.0/
Description:This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Projects

Funder:ARRS - Slovenian Research Agency
Project number:P1-0017-2020
Name:Modeliranje kemijskih procesov in lastnosti spojin

Funder:ARRS - Slovenian Research Agency
Project number:P1-0208-2022
Name:Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin

Funder:Other - Other funder or multiple funders
Funding programme:Young Researcher’s Program
Project number:39010

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