Exploring alternative pathways to target bacterial type II topoisomerases using NBTI antibacterials: beyond halogen-bonding interactions

Kokot, Maja (author), Novak, Doroteja (author), Zdovc, Irena (author), Anderluh, Marko (author), Hrast, Martina (author), Minovski, Nikola (author)

Novel bacterial topoisomerase inhibitors (NBTIs) are a new class of antibacterial agents that target bacterial type II topoisomerases (DNA gyrase and topoisomerase IV). Our recently disclosed crystal structure of an NBTI ligand in complex with DNA gyrase and DNA revealed that the halogen atom in the para position of the phenyl right hand side (RHS) moiety is able to establish strong symmetrical bifurcated halogen bonds with the enzyme; these are responsible for the excellent enzyme inhibitory potency and antibacterial activity of these NBTIs. To further assess the possibility of any alternative interactions (e.g., hydrogen-bonding and/or hydrophobic interactions), we introduced various non-halogen groups at the p-position of the phenyl RHS moiety. Considering the hydrophobic nature of amino acid residues delineating the NBTI’s binding pocket in bacterial topoisomerases, we demonstrated that designed NBTIs cannot establish any hydrogen-bonding interactions with the enzyme; hydrophobic interactions are feasible in all respects, while halogen-bonding interactions are apparently the most preferred.

• Language: English
• Keywords: DNA gyrase, topoisomerase IV, antibacterial, NBTIs, halogen-bonding interactions, hydrogen-bonding interactions, van der Waals interactions
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy; VF - Veterinary Faculty
• Publication date: 01.01.2023
• Year: 2023
• Number of pages: 15 str.
• Numbering: Vol. 12, no. 5, art. 930
• PID: 20.500.12556/RUL-153515
• UDC: 579
• ISSN on article: 2079-6382
• DOI: 10.3390/antibiotics12050930
• COBISS.SI-ID: 153123075
• Publication date in RUL: 11.01.2024

Record is a part of a journal

• Title: Antibiotics
• Shortened title: Antibiotics
• Publisher: MDPI
• ISSN: 2079-6382
• COBISS.SI-ID: 522975769

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
• Name: Modeliranje kemijskih procesov in lastnosti spojin

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