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Instruments / Technical Area	Publication Details	Published
NONE-No attached Diamond beamline	Fragment-based lead discovery strategies in antimicrobial drug discovery Monika I. Konaklieva , Balbina J. Plotkin Antibiotics 12 DOI: 10.3390/antibiotics12020315 Open Access Show Abstract ▼ Abstract: Fragment-based lead discovery (FBLD) is a powerful application for developing ligands as modulators of disease targets. This approach strategy involves identification of interactions between low-molecular weight compounds (100–300 Da) and their putative targets, often with low affinity (KD ~0.1–1 mM) interactions. The focus of this screening methodology is to optimize and streamline identification of fragments with higher ligand efficiency (LE) than typical high-throughput screening. The focus of this review is on the last half decade of fragment-based drug discovery strategies that have been used for antimicrobial drug discovery.	Feb 2023
I19-Small Molecule Single Crystal Diffraction	Tricyclic fused lactams by Mukaiyama cyclisation of phthalimides and evaluation of their biological activity Lewis T. Ibbotson , Kirsten Christensen , Miroslav Genov , Alexander Pretsch , Dagmar Pretsch , Mark G. Moloney Antibiotics 12 DOI: 10.3390/antibiotics12010009 Diamond Proposal Number(s): [20876] Open Access Show Abstract ▼ Abstract: We report that phthalimides may be cyclized using a Mukaiyama-type aldol coupling to give variously substituted fused lactam (1,2,3,9b-tetrahydro-5H-pyrrolo[2,1-a]isoindol-5-one) systems. This novel process shows a high level of regioselectivity for o-substituted phthalimides, dictated by steric and electronic factors, but not for m-substituted phthalimides. The initial aldol adduct is prone to elimination, giving 2,3-dihydro-5H-pyrrolo[2,1-a]isoindol-5-ones, and the initial cyclisation can be conducted in such a way that aldol cyclisation-elimination is achievable in a one-pot approach. The 2,3-dihydro-5H-pyrrolo[2,1-a]isoindol-5-ones possess cross conjugation and steric effects which significantly influence the reactivity of several functional groups, but conditions suitable for epoxidation, ester hydrolysis and amide formation, and reduction, which provide for ring manipulation, were identified. Many of the derived lactam systems, and especially the eliminated systems, show low solubility, which compromises biological activity, although in some cases, antibacterial and cytotoxic activity was found, and this new class of small molecule provides a useful skeleton for further elaboration and study.	Dec 2022
I04-1-Macromolecular Crystallography (fixed wavelength)	Studies on the reactions of biapenem with VIM metallo β-lactamases and the serine β-lactamase KPC-2 Anka Lucic , Tika R. Malla , Karina Calvopina , Catherine L. Tooke , Jurgen Brem , Michael A. Mcdonough , James Spencer , Christopher J. Schofield Antibiotics 11 DOI: 10.3390/antibiotics11030396 Diamond Proposal Number(s): [18069] Open Access Show Abstract ▼ Abstract: Carbapenems are important antibacterials and are both substrates and inhibitors of some β-lactamases. We report studies on the reaction of the unusual carbapenem biapenem, with the subclass B1 metallo-β-lactamases VIM-1 and VIM-2 and the class A serine-β-lactamase KPC-2. X-ray diffraction studies with VIM-2 crystals treated with biapenem reveal the opening of the β-lactam ring to form a mixture of the (2S)-imine and enamine complexed at the active site. NMR studies on the reactions of biapenem with VIM-1, VIM-2, and KPC-2 reveal the formation of hydrolysed enamine and (2R)- and (2S)-imine products. The combined results support the proposal that SBL/MBL-mediated carbapenem hydrolysis results in a mixture of tautomerizing enamine and (2R)- and (2S)-imine products, with the thermodynamically favoured (2S)-imine being the major observed species over a relatively long-time scale. The results suggest that prolonging the lifetimes of β-lactamase carbapenem complexes by optimising tautomerisation of the nascently formed enamine to the (2R)-imine and likely more stable (2S)-imine tautomer is of interest in developing improved carbapenems.	Mar 2022

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