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 ORCID: https://orcid.org/0000-0001-9014-3790 and Bax, Ben D. ORCID: https://orcid.org/0000-0003-1940-3785 2023. A 2.8 Å structure of zoliflodacin in a DNA cleavage complex with staphylococcus aureus DNA gyrase. International Journal of Molecular Sciences 24 (2) , 1634. 10.3390/ijms24021634

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Publisher:	MDPI
ISSN:	1422-0067
Date of First Compliant Deposit:	1 February 2023
Date of Acceptance:	7 January 2023
Last Modified:	06 Mar 2024 02:09
URI:	https://orca.cardiff.ac.uk/id/eprint/156431

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