Laponogov, I; Pan, X-S; Veselkov, DA; Cirz, RT; Wagman, A; Moser, HE; Fisher, LM; Sanderson, MR
(2016)
Exploring the active site of the Streptococcus pneumoniae topoisomerase IV-DNA cleavage complex with novel 7,8-bridged fluoroquinolones.
Open Biology, 6 (9).
ISSN 2046-2441
https://doi.org/10.1098/rsob.160157
SGUL Authors: Fisher, Larry Mark
Abstract
As part of a programme of synthesizing and investigating the biological properties of new fluoroquinolone antibacterials and their targeting of topoisomerase IV from Streptococcus pneumoniae, we have solved the X-ray structure of the complexes of two new 7,8-bridged fluoroquinolones (with restricted C7 group rotation favouring tight binding) in complex with the topoisomerase IV from S. pneumoniae and an 18-base-pair DNA binding site-the E-site-found by our DNA mapping studies to bind drug strongly in the presence of topoisomerase IV (Leo et al. 2005 J. Biol. Chem. 280, 14 252-14 263, doi:10.1074/jbc.M500156200). Although the degree of antibiotic resistance towards fluoroquinolones is much lower than that of β-lactams and a range of ribosome-bound antibiotics, there is a pressing need to increase the diversity of members of this successful clinically used class of drugs. The quinolone moiety of the new 7,8-bridged agents ACHN-245 and ACHN-454 binds similarly to that of clinafloxocin, levofloxacin, moxifloxacin and trovofloxacin but the cyclic scaffold offers the possibility of chemical modification to produce interactions with other topoisomerase residues at the active site.
Item Type: |
Article
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Additional Information: |
© 2016 The Authors.
Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited. |
Keywords: |
DNA topological experiments, MIC determinants, X-ray crystallography, drug design, protein–DNA complexes, topoisomerases, DNA topological experiments, MIC determinants, X-ray crystallography, drug design, protein–DNA complexes, topoisomerases |
SGUL Research Institute / Research Centre: |
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Cell Sciences (INCCCS) |
Journal or Publication Title: |
Open Biology |
ISSN: |
2046-2441 |
Language: |
ENG |
Dates: |
Date | Event |
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21 September 2016 | Published | 26 August 2016 | Accepted |
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Publisher License: |
Creative Commons: Attribution 4.0 |
Projects: |
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PubMed ID: |
27655731 |
![](http://static.pubmed.gov/portal/portal3rc.fcgi/2745237/img/27842) |
Go to PubMed abstract |
URI: |
https://openaccess.sgul.ac.uk/id/eprint/108332 |
Publisher's version: |
https://doi.org/10.1098/rsob.160157 |
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