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Potent DNA gyrase inhibitors bind asymmetrically to their target using symmetrical bifurcated halogen bonds
ID
Kolarič, Anja
(
Author
),
ID
Germe, Thomas
(
Author
),
ID
Hrast, Martina
(
Author
),
ID
Stevenson, Clare E. M.
(
Author
),
ID
Lawson, David M.
(
Author
),
ID
Burton, Nicolas P.
(
Author
),
ID
Vörös, Judit
(
Author
),
ID
Maxwell, Anthony
(
Author
),
ID
Minovski, Nikola
(
Author
),
ID
Anderluh, Marko
(
Author
)
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https://www.nature.com/articles/s41467-020-20405-8
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Abstract
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
Views:
592
Downloads:
56
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Record is a part of a journal
Title:
Nature communications
Shortened title:
Nat. Commun.
Publisher:
Nature Publishing Group
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
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
Funder:
UKRI - UK Research and Innovation
Funding programme:
BBSRC, Institute Strategic Programme
Project number:
BB/P012523/1
Funder:
WT - Wellcome Trust
Funding programme:
Investigator Award
Project number:
110072/Z/15/Z
Funder:
UKRI - UK Research and Innovation
Funding programme:
BBSRC
Project number:
BB/S507921/1
Name:
John Innes Centre Flexible Talent Mobility Account
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