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A 2.8 Å Structure of Zoliflodacin in a DNA Cleavage Complex with Staphylococcus aureus DNA Gyrase

Since 2000, some thirteen quinolones and fluoroquinolones have been developed and have come to market. The quinolones, one of the most successful classes of antibacterial drugs, stabilize DNA cleavage complexes with DNA gyrase and topoisomerase IV (topo IV), the two bacterial type IIA topoisomerases...

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Autores principales: Morgan, Harry, Lipka-Lloyd, Magdalena, Warren, Anna J., Hughes, Naomi, Holmes, John, Burton, Nicolas P., Mahenthiralingam, Eshwar, Bax, Ben D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9865888/
https://www.ncbi.nlm.nih.gov/pubmed/36675148
http://dx.doi.org/10.3390/ijms24021634
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author Morgan, Harry
Lipka-Lloyd, Magdalena
Warren, Anna J.
Hughes, Naomi
Holmes, John
Burton, Nicolas P.
Mahenthiralingam, Eshwar
Bax, Ben D.
author_facet Morgan, Harry
Lipka-Lloyd, Magdalena
Warren, Anna J.
Hughes, Naomi
Holmes, John
Burton, Nicolas P.
Mahenthiralingam, Eshwar
Bax, Ben D.
author_sort Morgan, Harry
collection PubMed
description Since 2000, some thirteen quinolones and fluoroquinolones have been developed and have come to market. The quinolones, one of the most successful classes of antibacterial drugs, stabilize DNA cleavage complexes with DNA gyrase and topoisomerase IV (topo IV), the two bacterial type IIA topoisomerases. The dual targeting of gyrase and topo IV helps decrease the likelihood of resistance developing. Here, we report on a 2.8 Å X-ray crystal structure, which shows that zoliflodacin, a spiropyrimidinetrione antibiotic, binds in the same DNA cleavage site(s) as quinolones, sterically blocking DNA religation. The structure shows that zoliflodacin interacts with highly conserved residues on GyrB (and does not use the quinolone water–metal ion bridge to GyrA), suggesting it may be more difficult for bacteria to develop target mediated resistance. We show that zoliflodacin has an MIC of 4 µg/mL against Acinetobacter baumannii (A. baumannii), an improvement of four-fold over its progenitor QPT-1. The current phase III clinical trial of zoliflodacin for gonorrhea is due to be read out in 2023. Zoliflodacin, together with the unrelated novel bacterial topoisomerase inhibitor gepotidacin, is likely to become the first entirely novel chemical entities approved against Gram-negative bacteria in the 21st century. Zoliflodacin may also become the progenitor of a new safer class of antibacterial drugs against other problematic Gram-negative bacteria.
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spelling pubmed-98658882023-01-22 A 2.8 Å Structure of Zoliflodacin in a DNA Cleavage Complex with Staphylococcus aureus DNA Gyrase Morgan, Harry Lipka-Lloyd, Magdalena Warren, Anna J. Hughes, Naomi Holmes, John Burton, Nicolas P. Mahenthiralingam, Eshwar Bax, Ben D. Int J Mol Sci Article Since 2000, some thirteen quinolones and fluoroquinolones have been developed and have come to market. The quinolones, one of the most successful classes of antibacterial drugs, stabilize DNA cleavage complexes with DNA gyrase and topoisomerase IV (topo IV), the two bacterial type IIA topoisomerases. The dual targeting of gyrase and topo IV helps decrease the likelihood of resistance developing. Here, we report on a 2.8 Å X-ray crystal structure, which shows that zoliflodacin, a spiropyrimidinetrione antibiotic, binds in the same DNA cleavage site(s) as quinolones, sterically blocking DNA religation. The structure shows that zoliflodacin interacts with highly conserved residues on GyrB (and does not use the quinolone water–metal ion bridge to GyrA), suggesting it may be more difficult for bacteria to develop target mediated resistance. We show that zoliflodacin has an MIC of 4 µg/mL against Acinetobacter baumannii (A. baumannii), an improvement of four-fold over its progenitor QPT-1. The current phase III clinical trial of zoliflodacin for gonorrhea is due to be read out in 2023. Zoliflodacin, together with the unrelated novel bacterial topoisomerase inhibitor gepotidacin, is likely to become the first entirely novel chemical entities approved against Gram-negative bacteria in the 21st century. Zoliflodacin may also become the progenitor of a new safer class of antibacterial drugs against other problematic Gram-negative bacteria. MDPI 2023-01-13 /pmc/articles/PMC9865888/ /pubmed/36675148 http://dx.doi.org/10.3390/ijms24021634 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Morgan, Harry
Lipka-Lloyd, Magdalena
Warren, Anna J.
Hughes, Naomi
Holmes, John
Burton, Nicolas P.
Mahenthiralingam, Eshwar
Bax, Ben D.
A 2.8 Å Structure of Zoliflodacin in a DNA Cleavage Complex with Staphylococcus aureus DNA Gyrase
title A 2.8 Å Structure of Zoliflodacin in a DNA Cleavage Complex with Staphylococcus aureus DNA Gyrase
title_full A 2.8 Å Structure of Zoliflodacin in a DNA Cleavage Complex with Staphylococcus aureus DNA Gyrase
title_fullStr A 2.8 Å Structure of Zoliflodacin in a DNA Cleavage Complex with Staphylococcus aureus DNA Gyrase
title_full_unstemmed A 2.8 Å Structure of Zoliflodacin in a DNA Cleavage Complex with Staphylococcus aureus DNA Gyrase
title_short A 2.8 Å Structure of Zoliflodacin in a DNA Cleavage Complex with Staphylococcus aureus DNA Gyrase
title_sort 2.8 å structure of zoliflodacin in a dna cleavage complex with staphylococcus aureus dna gyrase
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9865888/
https://www.ncbi.nlm.nih.gov/pubmed/36675148
http://dx.doi.org/10.3390/ijms24021634
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