Hybrid inhibitors of DNA gyrase A and B : design, synthesis and evaluation

Durcik, Martina (author), Skok, Žiga (author), Ilaš, Janez (author), Zidar, Nace (author), Zega, Anamarija (author), Szili, Petra (author), Draskovits, Gábor (author), Revesz, T. (author), Kikelj, Danijel (author), Nyerges, Ákos (author), Pál, Csaba (author), Peterlin-Mašič, Lucija (author), Tomašič, Tihomir (author)

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 3a has MICs of 0.5 µg/mL against Klebsiella pneumoniae, 4 µg/mL against Enterobacter cloacae, and 2 µg/mL against Escherichia coli. In addition, inhibition of mutant E. coli 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.

• Language: English
• Keywords: antibacterial, ciprofloxacin, DNA gyrase, dual inhibitor, hybrid
• 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: 17 str.
• Numbering: Vol. 13, iss. 1, art. 6
• PID: 20.500.12556/RUL-134779
• UDC: 615.4:54:615.015.8
• ISSN on article: 1999-4923
• DOI: 10.3390/pharmaceutics13010006
• COBISS.SI-ID: 44007939
• Publication date in RUL: 01.02.2022

Record is a part of a journal

• Title: Pharmaceutics
• Shortened title: Pharmaceutics
• Publisher: MDPI
• ISSN: 1999-4923
• COBISS.SI-ID: 517949977

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.
• Licensing start date: 01.01.2021

Secondary language

• Language: Slovenian
• Keywords: DNK giraze, ciprofloksacin, zaviralci, hibridi, bakterijska rezistenca, farmacevtska kemija