"The structural diversity and differences in metal utilisation by metallo-β-lactamases (MBLs) makes the discovery of a broad spectrum MBL inhibitors challenging. Optimised protein production and purification procedures (for all subclasses B1, B2 and B3 of MBLs) have been performed and their crystal structures have been obtained. Initially phosphonic acids were chosen for inhibitor discovery, however, in all cases the compounds were near inactive supporting the importance of both thiol and carboxylate groups for binding and inhibition. Additional MBL screens revealed the potential of using indole carboxylates for DC screens. Synthetic work on this family of compounds, yielded promising results with respect to applying DC chemistry (boronate ester exchange) on the 7- position of indole carboxylate, couple to analysis by x-ray crystallography. Rhodanine derived enethiol inhibitors of Metallo β-Lactamases: In this work, efficient methods were developed for the synthesis of analogies of the rhodanine ML302 and the ene-thiol ML302F, derived by hydrolysis of the former. The overall results revel that rhodanine derived species have potential as broad spectrum MBL inhibitors, and when combined with other results, also as serine β-Lactamase and penicillin binding protein inhibitors. Cyclic boronic and phosphonic acids: Recent work from the host laboratory has found that cyclic boronates are potent inhibitors, not only on MBLs, but also on SBLs, some of which also show weak activity against penicillin binding proteins. The syntheses of boronic acids was investigated via two independent routes involving: (a) Matteson’s homologation wherein boronic esters containing the chiral pinanediol auxiliary can undergo α-chloromethylene homologation to give α-chloroboronic esters which are further transformed to α-amino boronic esters, and (b) catalytic asymmetric hydroboration of aldimines. Pyridine, Pyrrole and Indole carboxylates: Synthetic methods were developed for the preparation of pyridine, pyrrole and indole carboxylates some of which showed broad spectrum activity with IC50 values <5nM (e.g. for VIM-2 at 200pM). Work in the Schofield group has led to one publication in Future Medicinal Chemistry [""The road to avibactam - the first clinically useful non-β-lactam working like a β-lactam"", 2016, 8, 1063-1084]. Work on rhodanine derived enethiols, pyridine, pyrrole and indole carboxylates, phosphonic and -boronic acids as ‘transition state analogue’ based inhibitors, as well as results from cross screening on different biological targets are currently in preparation and will be disseminated in the near future."
