Structurally optimized potent dual-targeting NBTI antibacterials with an enhanced bifurcated halogen-bonding propensity

Kokot, Maja (author), Weiss, Matjaž (author), Zdovc, Irena (author), Hrast, Martina (author), Anderluh, Marko (author), Minovski, Nikola (author)

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
• UDC: 615.4:54:579
• ISSN on article: 1948-5875
• DOI: 10.1021/acsmedchemlett.1c00345
• COBISS.SI-ID: 73185027
• Publication date in RUL: 29.09.2022

Record is a part of a journal

• Title: ACS medicinal chemistry letters
• Publisher: American Chemical Society
• ISSN: 1948-5875
• COBISS.SI-ID: 2959217

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• 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.