Rhodanine hydrolysis leads to potent thioenolate mediated metallo-ß-lactamase inhibition.
Nat Chem
; 6(12): 1084-90, 2014 Dec.
Article
in En
| MEDLINE
| ID: mdl-25411887
ABSTRACT
The use of ß-lactam antibiotics is compromised by resistance, which is provided by ß-lactamases belonging to both metallo (MBL)- and serine (SBL)-ß-lactamase subfamilies. The rhodanines are one of very few compound classes that inhibit penicillin-binding proteins (PBPs), SBLs and, as recently reported, MBLs. Here, we describe crystallographic analyses of the mechanism of inhibition of the clinically relevant VIM-2 MBL by a rhodanine, which reveal that the rhodanine ring undergoes hydrolysis to give a thioenolate. The thioenolate is found to bind via di-zinc chelation, mimicking the binding of intermediates in ß-lactam hydrolysis. Crystallization of VIM-2 in the presence of the intact rhodanine led to observation of a ternary complex of MBL, a thioenolate fragment and rhodanine. The crystallographic observations are supported by kinetic and biophysical studies, including (19)F NMR analyses, which reveal the rhodanine-derived thioenolate to be a potent broad-spectrum MBL inhibitor and a lead structure for the development of new types of clinically useful MBL inhibitors.
Full text:
1
Database:
MEDLINE
Main subject:
Rhodanine
/
Beta-Lactamase Inhibitors
Language:
En
Journal:
Nat Chem
Journal subject:
QUIMICA
Year:
2014
Type:
Article
Affiliation country:
United kingdom