Inhibition of IMP-1 metallo-beta-lactamase and sensitization of IMP-1-producing bacteria by thioester derivatives.
IMP-1 metallo-beta-lactamase is a transferable carbapenem-hydrolyzing enzyme found in some clinical isolates of Pseudomonas aeruginosa, Serratia marcescens and Klebsiella pneumoniae. Bacteria that express IMP-1 show significantly reduced sensitivity to carbapenems and other beta-lactam antibiotics. A series of thioester derivatives has been shown to competitively inhibit purified IMP-1. As substrates for IMP-1, the thioesters yielded thiol hydrolysis 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 modification to improve their activity in less permeable organisms such as Pseudomonas and Serratia. Nonetheless, the thioester IMP-1 inhibitors offer an encouraging start to overcoming metallo-beta-lactamase-mediated resistance in bacteria.
Hammond
G G
GG
Department of Biochemistry, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065-0900, USA.
Huber
J L
JL
Greenlee
M L
ML
Laub
J B
JB
Young
K
K
Silver
L L
LL
Balkovec
J M
JM
Pryor
K D
KD
Wu
J K
JK
Leiting
B
B
Pompliano
D L
DL
Toney
J H
JH
D001419:Bacteria / Q000187:drug effects* / Q000201:enzymology; D015780:Carbapenems / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D013438:Sulfhydryl Compounds / Q000494:pharmacology*; D065093:beta-Lactamase Inhibitors
D015780:Carbapenems; D004791:Enzyme Inhibitors; D013438:Sulfhydryl Compounds; D065093:beta-Lactamase Inhibitors