Inhibition of IMP-1 metallo-beta-lactamase and sensitization of TMP-1-producing bacteria by thioester derivatives

IMP-1 metallo-beta-lactamase is a transferable carbapenem-hydrolyzing enzym e found in some clinical isolates of Pseudomonas aeruginosa, Serratia marce scens and Klebsiella pneumoniae. Bacteria that express IMP-1 show significa ntly reduced sensitivity to carbapenems and other beta-lactam antibiotics. A series of thioester derivatives has been shown to competitively inhibit p urified IMP-1. As substrates for IMP-1, the thioesters yielded thiol hydrol ysis products which themselves were reversible competitive inhibitors. The thioesters also increased sensitivity to the carbapenem L-742,728 in an IMP -1-producing laboratory stain of Escherichia coli, but will need further mo dification to improve their activity in less permeable organisms such as Ps eudomonas and Serratia. Nonetheless, the thioester IMP-1 inhibitors offer a n encouraging start to overcoming merallo-beta-lactamase-mediated resistanc e in bacteria. (C) 1994 Federation of European Microbiological Societies. P ublished by Elsevier Science B.V. All rights reserved.