IMP-1 metallo-␤-lactamase (class B) is a plasmid-borne zinc metalloenzyme that efficiently hydrolyzes ␤-lactam antibiotics, including carbapenems, rendering them ineffective. Because IMP-1 has been found in several clinically important carbapenem-resistant pathogens, there is a need for inhibitors of this enzyme that could protect broad spectrum antibiotics such as imipenem from hydrolysis and thus extend their utility. We have identified a series of 2,3-(S,S)-disubstituted succinic acids that are potent inhibitors of IMP-1. Determination of high resolution crystal structures and molecular modeling of succinic acid inhibitor complexes with IMP-1 has allowed an understanding of the potency, stereochemistry, and structure-activity relationships of these inhibitors.Carbapenems such as imipenem (Scheme 1) have proven useful for the treatment of a variety of Gram-negative and Gram-positive infections (1, 2). Carbapenems and other ␤-lactam antibiotics covalently modify penicillin-binding proteins (PBPs) 1 involved in the peptidoglycan biosynthetic pathway of cell wall assembly in bacteria (3, 4). Resistance to carbapenems can arise because of acquisition of low affinity PBPs (3) (e.g. PBP2a of Staphylococcus aureus), altered membrane permeability (5), and expression of class A, B, and D ␤-lactamases (6 -10). Class B ␤-lactamases (metallo-␤-lactamases or MBLs) can hydrolyze a wide variety of substrates of the ␤-lactam class, including carbapenems, penicillins, and cephalosporins, rendering them ineffective as antibiotics.The IMP-1 gene encoding an MBL has been identified on a plasmid and in Japan has transferred among clinical isolates such as Pseudomonas aeruginosa (11,12), Klebsiella pneumoniae, Serratia marcescens, and other members of the Enterobacteriaceae (13,14). In addition, carbapenem-resistant clinical isolates expressing MBLs related to IMP-1 have been identified recently in Singapore (15), Italy (16), and Hong Kong (10). Such reports of plasmid-borne imipenem resistance highlight the need for inhibitors of IMP-1 that can restore the activity of carbapenems in resistant bacteria.Several classes of MBL inhibitors have been reported (for reviews, see Refs. 17 and 18)) including phenazines (19), trifluoromethyl alcohol and ketone derivatives of L-and D-alanine (20), thioesters (18, 21-23), thiols (24 -28), biphenyl tetrazoles (29, 30), and amino acid-derived hydroxamates (31). Biphenyl tetrazoles have been shown to reverse imipenem resistance in a clinical isolate of Bacteroides fragilis (29), and thioesters have been shown to reverse resistance to the carbapenem L-742,728 in a laboratory strain of Escherichia coli expressing IMP-1 (32). A 1␤-methylcarbapenem substituted at C-2 with a benzothienylthio moiety has been reported to be a potent IMP-1 inhibitor that can reverse resistance to imipenem in an IMP-1-producing strain of Serratia marcescens (33). Although the inhibitors described above have been reported to have good activity against a specific MBL, only certain thiols (e.g. SB 264218) exhibit broad spe...

BPT inhibitors can sensitize a resistant B. fragilis clinical isolate expressing metallo-beta-lactamase to the antibiotics imipenem or penicillin G but not to rifampicin.

No abstract

No abstract

An important mechanism of bacterial resistance to β-lactam antibiotics is inactivation by β-lactam-hydrolyzing enzymes (β-lactamases). The evolution of the extended-spectrum β-lactamases (ESBLs) is associated with extensive use of β-lactam antibiotics, particularly cephalosporins, and is a serious threat to therapeutic efficacy. ESBLs and broad-spectrum β-lactamases (BDSBLs) are plasmid-mediated class A enzymes produced by gram-negative pathogens, principallyEscherichia coli and Klebsiella pneumoniae. MK-0826 was highly potent against all ESBL- and BDSBL-producingK. pneumoniae and E. coli clinical isolates tested (MIC range, 0.008 to 0.12 μg/ml). In E. coli, this activity was associated with high-affinity binding to penicillin-binding proteins 2 and 3. When the inoculum level was increased 10-fold, increasing the amount of β-lactamase present, the MK-0826 MIC range increased to 0.008 to 1 μg/ml. By comparison, similar observations were made with meropenem while imipenem MICs were usually less affected. Not surprisingly, MIC increases with noncarbapenem β-lactams were generally substantially greater, resulting in resistance in many cases. E. coli strains that produce chromosomal (Bush group 1) β-lactamase served as controls. All three carbapenems were subject to an inoculum effect with the majority of the BDSBL- and ESBL-producers but not the Bush group 1 strains, implying some effect of the plasmid-borne enzymes on potency. Importantly, MK-0826 MICs remained at or below 1 μg/ml under all test conditions.