Potent DNA gyrase inhibitors bind asymmetrically to their target using symmetrical bifurcated halogen bonds

Kolarič, Anja (author), Germe, Thomas (author), Hrast, Martina (author), Stevenson, Clare E. M. (author), Lawson, David M. (author), Burton, Nicolas P. (author), Vörös, Judit (author), Maxwell, Anthony (author), Minovski, Nikola (author), Anderluh, Marko (author)

Novel bacterial type II topoisomerase inhibitors (NBTIs) stabilize single-strand DNA cleavage breaks by DNA gyrase but their exact mechanism of action has remained hypothetical until now. We have designed a small library of NBTIs with an improved DNA gyrase-binding moiety resulting in low nanomolar inhibition and very potent antibacterial activity. They stabilize single-stranded cleavage complexes and, importantly, we have obtained the crystal structure where an NBTI binds gyrase-DNA in a single conformation lacking apparent static disorder. This directly proves the previously postulated NBTI mechanism of action and shows that they stabilize single-strand cleavage through asymmetric intercalation with a shift of the scissile phosphate. This crystal stucture shows that the chlorine forms a halogen bond with the backbone carbonyls of the two symmetry-related Ala68 residues. To the best of our knowledge, such a so-called symmetrical bifurcated halogen bond has not been identified in a biological system until now.

• Language: English
• Keywords: antibacterials, DNA gyrase inhibitors, drug discovery, Staphylococcus aureus, intercalators, novel bacterial topoisomerase inhibitors, NBTIs, symmetrical bifurcated halogen bonds, crystal structure, novel NBTIs mechanism of action, antimicrobials, DNA-binding proteins, drug development, X-ray crystallography
• 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: 13 str.
• Numbering: Vol. 12, art. 150
• PID: 20.500.12556/RUL-144808
• UDC: 577
• ISSN on article: 2041-1723
• DOI: 10.1038/s41467-020-20405-8
• COBISS.SI-ID: 46272259
• Publication date in RUL: 14.03.2023

Record is a part of a journal

• Title: Nature communications
• Shortened title: Nat. commun.
• Publisher: Springer Nature
• ISSN: 2041-1723
• COBISS.SI-ID: 2315876

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.

Secondary language

• Language: Slovenian
• Keywords: biokemija, DNK, Escherichia coli, zaviralci