Abstract
Metallo-β-lactamases (MBLs) enable bacterial resistance to almost all classes of β-lactam antibiotics. We report studies on enethiol containing MBL inhibitors, which were prepared by rhodanine hydrolysis. The enethiols inhibit MBLs from different subclasses. Crystallographic analyses reveal that the enethiol sulphur displaces the di-Zn(II) ion bridging ‘hydrolytic’ water. In some, but not all, cases biophysical analyses provide evidence that rhodanine/enethiol inhibition involves formation of a ternary MBL enethiol rhodanine complex. The results demonstrate how low molecular weight active site Zn(II) chelating compounds can inhibit a range of clinically relevant MBLs and provide additional evidence for the potential of rhodanines to be hydrolysed to potent inhibitors of MBL protein fold and, maybe, other metallo-enzymes, perhaps contributing to the complex biological effects of rhodanines. The results imply that any medicinal chemistry studies employing rhodanines (and related scaffolds) as inhibitors should as a matter of course include testing of their hydrolysis products.
Highlights
Following the clinical introduction of the penicillins in the 1940s, b-lactam antibiotics came to be, and remain, amongst the most important medicines in use.[1]
As part of this work we tested the potency of the rhodanine ML302 (Scheme 1), which was identified following a high-throughput screen, as inhibitor of VIM-2 and IMP-1.23 Unexpectedly, we found that ML302 undergoes hydrolysis to give the enethiol fragment, ML302F (Scheme 1), which inhibits MBLs via active site Zn(II) ion chelation; in the case of VIM-2 we observed the unusual formation of a ternary complex between the enzyme and two different ligands, ML302 and ML302F.24
The overall results reveal that rhodanine derived species have potential as broad spectrum MBL inhibitors, which might be in part due to the proposal that enethiol carboxylate binding mimics that of b-lactam hydrolysis product (Fig. S13)
Summary
Following the clinical introduction of the penicillins in the 1940s, b-lactam antibiotics came to be, and remain, amongst the most important medicines in use.[1]. The class B MBLs all utilise one (subclass B2 and some B3) or two (subclasses B1 and some B3) Zn(II) ions at their active site.[18]. As part of this work we tested the potency of the rhodanine ML302 (Scheme 1), which was identified following a high-throughput screen, as inhibitor of VIM-2 and IMP-1.23 Unexpectedly, we found that ML302 undergoes hydrolysis to give the enethiol fragment, ML302F (Scheme 1), which inhibits MBLs via active site Zn(II) ion chelation; in the case of VIM-2 we observed the unusual formation of a ternary complex between the enzyme and two different ligands, ML302 and ML302F.24. As part of this work we tested the potency of the rhodanine ML302 (Scheme 1), which was identified following a high-throughput screen, as inhibitor of VIM-2 and IMP-1.23 Unexpectedly, we found that ML302 undergoes hydrolysis to give the enethiol fragment, ML302F (Scheme 1), which inhibits MBLs via active site Zn(II) ion chelation; in the case of VIM-2 we observed the unusual formation of a ternary complex between the enzyme and two different ligands, ML302 and ML302F.24 We describe structure activity relationship and biophysical studies on the rhodanine derived enethiol MBL inhibitors.[25]
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