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Instruments / Technical Area	Publication Details	Published	Actions
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Penicillanic acid sulfones inactivate the extended-spectrum β-lactamase CTX-M-15 through formation of a serine-lysine cross-link: an alternative mechanism of β-lactamase inhibition Philip Hinchliffe , Catherine L. Tooke , Christopher R. Bethel , Benlian Wang , Christopher Arthur , Kate J. Heesom , Stuart Shapiro , Daniela M. Schlatzer , Krisztina M. Papp-Wallace , Robert A. Bonomo , James Spencer Mbio DOI: 10.1128/mbio.01793-21 Diamond Proposal Number(s): [23269] Open Access Show Abstract ▼ Abstract: β-Lactamases hydrolyze β-lactam antibiotics and are major determinants of antibiotic resistance in Gram-negative pathogens. Enmetazobactam (formerly AAI101) and tazobactam are penicillanic acid sulfone (PAS) β-lactamase inhibitors that differ by an additional methyl group on the triazole ring of enmetazobactam, rendering it zwitterionic. In this study, ultrahigh-resolution X-ray crystal structures and mass spectrometry revealed the mechanism of PAS inhibition of CTX-M-15, an extended-spectrum β-lactamase (ESBL) globally disseminated among Enterobacterales. CTX-M-15 crystals grown in the presence of enmetazobactam or tazobactam revealed loss of the Ser70 hydroxyl group and formation of a lysinoalanine cross-link between Lys73 and Ser70, two residues critical for catalysis. Moreover, the residue at position 70 undergoes epimerization, resulting in formation of a D-amino acid. Cocrystallization of enmetazobactam or tazobactam with CTX-M-15 with a Glu166Gln mutant revealed the same cross-link, indicating that this modification is not dependent on Glu166-catalyzed deacylation of the PAS-acylenzyme. A cocrystal structure of enmetazobactam with CTX-M-15 with a Lys73Ala mutation indicates that epimerization can occur without cross-link formation and positions the Ser70 Cβ closer to Lys73, likely facilitating formation of the Ser70-Lys73 cross-link. A crystal structure of a tazobactam-derived imine intermediate covalently linked to Ser70, obtained after 30 min of exposure of CTX-M-15 crystals to tazobactam, supports formation of an initial acylenzyme by PAS inhibitors on reaction with CTX-M-15. These data rationalize earlier results showing CTX-M-15 deactivation by PAS inhibitors to involve loss of protein mass, and they identify a distinct mechanism of β-lactamase inhibition by these agents.	May 2022
I04-1-Macromolecular Crystallography (fixed wavelength)	Construction of a shape‐diverse fragment set: Design, synthesis and screen against Aurora‐A kinase Rong Zhang , Patrick J. Mcintyre , Patrick M. Collins , Daniel J. Foley , Christopher Arthur , Frank Von Delft , Richard Bayliss , Stuart Warriner , Adam Nelson Chemistry – A European Journal 73 DOI: 10.1002/chem.201900815 Diamond Proposal Number(s): [14331] Show Abstract ▼ Abstract: Historically, chemists have explored chemical space in a highly uneven and unsystematic manner. As an example, the shape diversity of existing fragment sets does not generally reflect that of all theoretically possible fragments. To assess experimentally the added value of increased three dimensionality, a shape‐diverse fragment set was designed and collated. The set was assembled by both using commercially available fragments and harnessing unified synthetic approaches to sp3‐rich molecular scaffolds. The resulting set of 80 fragments was highly three‐dimensional, and its shape diversity was significantly enriched by twenty synthesised fragments. The fragment set was screened by high‐throughput protein crystallography against Aurora‐A kinase, revealing four hits that targeted the binding site of allosteric regulators. In the longer term, it is envisaged that the fragment set could be screened against a range of functionally diverse proteins, allowing the added value of more shape‐diverse screening collections to be more fully assessed.	Apr 2019

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