Stereochemically altered cephalosporins as potent inhibitors of New Delhi metallo-β-lactamases

In Vitro and In Vivo Development of a β-Lactam-Metallo-β-Lactamase Inhibitor: Targeting Carbapenem-Resistant Enterobacterales

“…32 An area gaining traction is the employment of BL conjugates as prodrugs and inhibitors, forming a relatively stable enzymehydrolyzed product complex to target the MBL. 21,33,34 In this study, our novel approach was to covalently attach a wellbinding metal/zinc chelator to a BL scaffold (cephalosporin) in order to improve selectivity and biodistribution of the chelator. This approach gives both compounds an equal chance to reach the bacterial cell wall-producing target enzymes, thereby providing a lethal duo of high specificity to eradicate the bacterial infection.…”

“…A promising method to selectively target the MBLs’ mode of action is via the use of metal ion chelators that remove the essential zinc ions from the active site of the MBL enzyme. , Several scaffolds including N , N , N ′, N ′-tetrakis­(2-pyridinylmethyl)-1,2-ethanediamine (TPEN) and analogues, thiosemicarbazone, 1,4,7,10-tetraazacyclododecane (DOTA) analogues, , 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), 2-picolinic acid, phosphonates rhodanine, thioenolates, magnalol, tris-picolylamines, N -acylhydrazone, 2,6-pyridine dicarboxylates (H 2 dpa’s), and 1,2,4-triazole-3-thione, have shown good activity against the New Delhi metallo β-lactamase (NDM-1) and the Verona integron-encoded MBL (VIM-2) expressing bacteria, partially restoring meropenem activity. In many cases, these chelators have been conjugated with dipeptides that mimic the bacterial cell wall sequence.…”

Small-molecule inhibitors of bacterial-producing metallo-β-lactamases: insights into their resistance mechanisms and biochemical analyses of their activities

“…The first BLs, AmpC cephalosporinase (chromosomally encoded), were isolated from E. coli in the early 1940s. 4,46,47 As early BLs, they contributed to the development of resistance toward the first β-lactam antibiotic, penicillin. Two decades later, scientists discovered an E. coli-derived penicillinase called TEM-1, which is part of a novel category of transferable narrow-spectrum BL (NSBL).…”

“…The high biocompatibility on mammalian cells was indicated after treating HEK 293 cell lines with the compound, where the NOAEL concentration was up to 100 μM. 46 Chen and colleagues reported the synthesis of a dithiocarbamate compound incorporating a copper (Cu) ion, SA09-Cu (S25), which had a novel inhibition mechanism for MBLs. S25 not only inhibited NDM-1 effectively (with IC 50 value = 0.096 μM), but it also synergized well with meropenem.…”

β-Lactamase-Mediated Fragmentation: Historical Perspectives and Recent Advances in Diagnostics, Imaging, and Antibacterial Design

“…Finally, a report from Hu and colleagues earlier this year disclosed a new class of MBLIs featuring a unique trans-cephalosporin scaffold (Figure 15). 161 We previously described a report using a similar scaffold for development of BlaC-selective fluorogenic probes; 61 the authors discovered that this stereochemistry significantly impaired turnover by NDM-1 and postulated that this scaffold could be combined with a 3′-thiobenzoyl substituent (previously demonstrated to inhibit NDM-1 with conventional cephalosporins) to achieve more potent inhibitors of MBLs. 162 Mechanistic evaluation of the inhibitor library suggested that activity correlated with more electronegative groups at the C-3′ position; subsequent X-ray crystallography studies confirmed the inhibitor forms a stable complex with NDM-1 following hydrolysis and subsequent elimination of the leaving group, with the imine nitrogen and trans C-7 alkoxy group both forming important interactions with active site residues.…”