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Instruments / Technical Area	Publication Details	Published	Actions
I04-Macromolecular Crystallography	Potent DNA gyrase inhibitors bind asymmetrically to their target using symmetrical bifurcated halogen bonds Anja Kolarič , Thomas Germe , Martina Hrast , Clare E. M. Stevenson , David M. Lawson , Nicolas P. Burton , Judit Voros , Anthony Maxwell , Nikola Minovski , Marko Anderluh Nature Communications 12 DOI: 10.1038/s41467-020-20405-8 Diamond Proposal Number(s): [18565] Open Access Show Abstract ▼ Abstract: Novel bacterial type II topoisomerase inhibitors (NBTIs) stabilize single-strand DNA cleavage breaks by DNA gyrase but their exact mechanism of action has remained hypothetical until now. We have designed a small library of NBTIs with an improved DNA gyrase-binding moiety resulting in low nanomolar inhibition and very potent antibacterial activity. They stabilize single-stranded cleavage complexes and, importantly, we have obtained the crystal structure where an NBTI binds gyrase–DNA in a single conformation lacking apparent static disorder. This directly proves the previously postulated NBTI mechanism of action and shows that they stabilize single-strand cleavage through asymmetric intercalation with a shift of the scissile phosphate. This crystal stucture shows that the chlorine forms a halogen bond with the backbone carbonyls of the two symmetry-related Ala68 residues. To the best of our knowledge, such a so-called symmetrical bifurcated halogen bond has not been identified in a biological system until now.	Jan 2021
I03-Macromolecular Crystallography	A new class of antibacterials, the imidazopyrazinones, reveal structural transitions involved in DNA gyrase poisoning and mechanisms of resistance Thomas Germe , Judit Voros , Frederic Jeannot , Thomas Taillier , Robert A. Stavenger , Eric Bacqué , Anthony Maxwell , Benjamin D. Bax Nucleic Acids Research 16 DOI: 10.1093/nar/gky181 Diamond Proposal Number(s): [5799] Open Access Show Abstract ▼ 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.	Mar 2018

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