Biochemistry, volume 58, issue 44, pages 4447-4455
Bimodal Actions of a Naphthyridone/Aminopiperidine-Based Antibacterial That Targets Gyrase and Topoisomerase IV
1
Department of Diseases of the Developing World, GlaxoSmithKline, Parque Tecnológico de Madrid, Calle de Severo Ochoa, 2, 28760 Tres Cantos, Madrid, Spain
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2
Laboratory of Single Molecule Biophysics, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20982, United States
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3
Infectious Diseases Discovery, Medicines Opportunities Research Unit, GlaxoSmithKline, Collegeville, Pennsylvania 19426, United States
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4
VA Tennessee Valley Healthcare System, Nashville, Tennessee 37212, United States
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Publication type: Journal Article
Publication date: 2019-10-16
Journal:
Biochemistry
Quartile SCImago
Q1
Quartile WOS
Q3
Impact factor: 2.9
ISSN: 00062960, 15204995
PubMed ID:
31617352
Biochemistry
Abstract
Gyrase and topoisomerase IV are the targets of fluoroquinolone antibacterials. However, the rise in antimicrobial resistance has undermined the clinical use of this important drug class. Therefore, it is critical to identify new agents that maintain activity against fluoroquinolone-resistant strains. One approach is to develop non-fluoroquinolone drugs that also target gyrase and topoisomerase IV, but interact differently with the enzymes. This has led to the development of the "novel bacterial topoisomerase inhibitor" (NBTI) class of antibacterials. Despite the clinical potential of NBTIs, there is a relative paucity of data describing their mechanism of action against bacterial type II topoisomerases. Consequently, we characterized the activity of GSK126, a napthyridone/aminopiperidine-based NBTI, against a variety of Gram-positive and Gram-negative bacterial type II topoisomerases including gyrase from Mycobacterium tuberculosis, and gyrase and topoisomerase IV from Bacillus anthracis and Escherichia coli. GSK126 enhanced single-stranded DNA cleavage and suppressed double-stranded cleavage mediated by these enzymes. It was also a potent inhibitor of gyrase-catalyzed DNA supercoiling and topoisomerase IV-catalyzed decatenation. Thus, GSK126 displays a similar bimodal mechanism of action across a variety of species. In contrast, GSK126 displayed a variable ability to overcome fluoroquinolone resistance mutations across these same species. Our results suggest that NBTIs elicit their antibacterial effects by two different mechanisms: inhibition of gyrase/topoisomerase IV catalytic activity or enhancement of enzyme-mediated DNA cleavage. Furthermore, the relative importance of these two mechanisms appears to differ from species to species. Therefore, we propose that the mechanistic basis for the antibacterial properties of NBTIs is bimodal in nature.
Citations by journals
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Antimicrobial Agents and Chemotherapy
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2 publications, 12.5%
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ACS Infectious Diseases
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2 publications, 12.5%
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International Journal of Molecular Sciences
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ACS Medicinal Chemistry Letters
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Journal of Medicinal Chemistry
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2 publications, 12.5%
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Pharmaceutical patent analyst, 1, 6.25%
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1 publication, 6.25%
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Journal of the Electrochemical Society
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Journal of the Electrochemical Society
1 publication, 6.25%
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1 publication, 6.25%
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European Journal of Medicinal Chemistry
1 publication, 6.25%
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Citations by publishers
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6
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American Chemical Society (ACS)
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American Chemical Society (ACS)
6 publications, 37.5%
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American Society for Microbiology
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2 publications, 12.5%
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Multidisciplinary Digital Publishing Institute (MDPI)
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2 publications, 12.5%
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Future Science
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Future Science, 1, 6.25%
Future Science
1 publication, 6.25%
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The Electrochemical Society
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The Electrochemical Society
1 publication, 6.25%
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Frontiers Media S.A.
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Frontiers Media S.A.
1 publication, 6.25%
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Elsevier
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Elsevier
1 publication, 6.25%
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- We do not take into account publications that without a DOI.
- Statistics recalculated only for publications connected to researchers, organizations and labs registered on the platform.
- Statistics recalculated weekly.
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Gibson E. G. et al. Bimodal Actions of a Naphthyridone/Aminopiperidine-Based Antibacterial That Targets Gyrase and Topoisomerase IV // Biochemistry. 2019. Vol. 58. No. 44. pp. 4447-4455.
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Gibson E. G., Oviatt A. A., Cacho Izquierdo M., Neuman K. C., CHAN P. F., Osheroff N. Bimodal Actions of a Naphthyridone/Aminopiperidine-Based Antibacterial That Targets Gyrase and Topoisomerase IV // Biochemistry. 2019. Vol. 58. No. 44. pp. 4447-4455.
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TY - JOUR
DO - 10.1021/acs.biochem.9b00805
UR - https://doi.org/10.1021%2Facs.biochem.9b00805
TI - Bimodal Actions of a Naphthyridone/Aminopiperidine-Based Antibacterial That Targets Gyrase and Topoisomerase IV
T2 - Biochemistry
AU - CHAN, PAN F.
AU - Gibson, Elizabeth G
AU - Oviatt, Alexandria A
AU - Neuman, Keir C.
AU - Osheroff, Neil
AU - Cacho Izquierdo, Mónica
PY - 2019
DA - 2019/10/16 00:00:00
PB - American Chemical Society (ACS)
SP - 4447-4455
IS - 44
VL - 58
PMID - 31617352
SN - 0006-2960
SN - 1520-4995
ER -
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@article{2019_Gibson,
author = {PAN F. CHAN and Elizabeth G Gibson and Alexandria A Oviatt and Keir C. Neuman and Neil Osheroff and Mónica Cacho Izquierdo},
title = {Bimodal Actions of a Naphthyridone/Aminopiperidine-Based Antibacterial That Targets Gyrase and Topoisomerase IV},
journal = {Biochemistry},
year = {2019},
volume = {58},
publisher = {American Chemical Society (ACS)},
month = {oct},
url = {https://doi.org/10.1021%2Facs.biochem.9b00805},
number = {44},
pages = {4447--4455},
doi = {10.1021/acs.biochem.9b00805}
}
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Gibson, Elizabeth G., et al. “Bimodal Actions of a Naphthyridone/Aminopiperidine-Based Antibacterial That Targets Gyrase and Topoisomerase IV.” Biochemistry, vol. 58, no. 44, Oct. 2019, pp. 4447-4455. https://doi.org/10.1021%2Facs.biochem.9b00805.