Exploring the active site of the Streptococcus pneumoniae topoisomerase IV–DNA cleavage complex with novel 7,8-bridged fluoroquinolones
Author(s)
Type
Journal Article
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.
Date Issued
2016-09
Date Acceptance
2016-08-26
Citation
Open Biology, 2016, 6 (9)
ISSN
2046-2441
Publisher
The Royal Society
Journal / Book Title
Open Biology
Volume
6
Issue
9
Copyright Statement
© 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.
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.
License URL
Identifier
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000385434300005&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=a2bf6146997ec60c407a63945d4e92bb
Subjects
Biochemistry & Molecular Biology
BREAKAGE-REUNION DOMAIN
CRYSTALLIZATION
CRYSTAL-STRUCTURE
DETERMINANTS
DNA topological experiments
drug design
GYRASE
INHIBITION
KLEBSIELLA-PNEUMONIAE
Life Sciences & Biomedicine
MECHANISM
MIC determinants
protein-DNA complexes
Science & Technology
STRUCTURAL BASIS
topoisomerases
WILD-TYPE
X-ray crystallography
Publication Status
Published
Article Number
160157
Date Publish Online
2016-09-01