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

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.

Keywords

NBTIs;DNA gyrase;topoisomerase IV;bifurcated halogen bonds;dual targeting;

Data

Language: English
Year of publishing:
Typology: 1.01 - Original Scientific Article
Organization: UL FFA - Faculty of Pharmacy
UDC: 615.4:54:579
COBISS: 73185027 Link will open in a new window
ISSN: 1948-5875
Views: 3
Downloads: 0
Average score: 0 (0 votes)
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Other data

Secondary language: English
Secondary keywords: Farmacevtska kemija;Patogeni;Encimska aktivnost;
Type (COBISS): Article
Pages: str. 1478-1485
Volume: ǂVol. ǂ12
Issue: ǂiss. ǂ9
Chronology: 2021
DOI: 10.1021/acsmedchemlett.1c00345
ID: 16608113