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A new class of antibacterials, the imidazopyrazinones, reveal structural transitions involved in DNA gyrase poisoning and mechanisms of resistance

Germe, Thomas, Vörös, Judit, Jeannot, Frederic, Taillier, Thomas, Stavenger, Robert A, Bacqué, Eric, Maxwell, Anthony and Bax, Benjamin 2018. A new class of antibacterials, the imidazopyrazinones, reveal structural transitions involved in DNA gyrase poisoning and mechanisms of resistance. Nucleic Acids Research 46 (8) , pp. 4114-4128. 10.1093/nar/gky181

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Abstract

Imidazopyrazinones (IPYs) are a new class of compounds that target bacterial topoisomerases as a basis for their antibacterial activity. We have characterized the mechanism of these compounds through structural/mechanistic studies showing they bind and stabilize a cleavage complex between DNA gyrase and DNA (‘poisoning’) in an analogous fashion to fluoroquinolones, but without the requirement for the water–metal–ion bridge. Biochemical experiments and structural studies of cleavage complexes of IPYs compared with an uncleaved gyrase–DNA complex, reveal conformational transitions coupled to DNA cleavage at the DNA gate. These involve movement at the GyrA interface and tilting of the TOPRIM domains toward the scissile phosphate coupled to capture of the catalytic metal ion. Our experiments show that these structural transitions are involved generally in poisoning of gyrase by therapeutic compounds and resemble those undergone by the enzyme during its adenosine triphosphate-coupled strand-passage cycle. In addition to resistance mutations affecting residues that directly interact with the compounds, we characterized a mutant (D82N) that inhibits formation of the cleavage complex by the unpoisoned enzyme. The D82N mutant appears to act by stabilizing the binary conformation of DNA gyrase with uncleaved DNA without direct interaction with the compounds. This provides general insight into the resistance mechanisms to antibiotics targeting bacterial type II topoisomerases.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: Oxford University Press (OUP): Policy C - Option B / Oxford University Press
ISSN: 0305-1048
Date of First Compliant Deposit: 8 May 2018
Date of Acceptance: 2 March 2018
Last Modified: 09 May 2018 11:03
URI: http://orca.cf.ac.uk/id/eprint/111249

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