Identification of Cisplatin and Palladium(II) Complexes as Potent Metallo-β-lactamase Inhibitors for Targeting Carbapenem-Resistant Enterobacteriaceae

Abstract

The emergence and prevalence of carbapenem-resistant bacterial infection have seriously threatened the clinical use of almost all β-lactam antibacterials. The development of effective metallo-β-lactamase (MβL) inhibitors to restore the existing antibiotics efficacy is an ideal alternative. Although several types of serine-β-lactamase inhibitors have been successfully developed and used in clinical settings, MβL inhibitors are not clinically available to date. Herein, we identified that cisplatin and Pd(II) complexes are potent broad-spectrum inhibitors of the B1 and B2 subclasses of MβLs and effectively revived Meropenem efficacy against MβL-expressing bacteria in vitro. Enzyme kinetics, thermodynamics, inductively coupled plasma atomic emission spectrometry (ICP-AES), matrix-assisted laser desorption/ionization-time of flight-mass spectrometry (MALDI-TOF-MS), and sitedirected mutation assays revealed that these metal complexes irreversibly inhibited NDM-1 through a novel inhibition mode involving binding to Cys208 and displacing one Zn(II) ion of the enzyme with one Pt(II) containing two NH 3 's or one Pd(II) ion. Importantly, the combination therapy of Meropenem and metal complexes significantly suppressed the development of higher-level resistance in bacteria producing NDM-1, also effectively reduced the bacterial burden in liver and spleen of mice infected by carbapenem-resistant Enterobacteriaceae producing NDM-1. These findings will offer potential lead compounds for the further development of clinically useful inhibitors targeting MβLs.

Hydroxamate and thiosemicarbazone: Two highly promising scaffolds for the development of SARS-CoV-2 antivirals

“…5 a), suggesting the inactivation rate follows pseudo-first-order rate kinetics. These results imply that the hydroxamate may covalently bind to the target [38] . The K obs (observed rate constant) were fitted against inhibitor concentration by nonlinear regression to calculate K I (the concentration of inacti-vator at the half-maximum inactivation rate constant), k inact , and k inact /K I values, which are 1.18±0.43 µM, 0.0075±0.0005 s −1 , and 6.4x10 3 M −1 s −1 , respectively [37] .…”

“…To further study the inhibition mode of the hydroxamates and thiosemicarbazones on M pro , 1a and 2b were chosen to determine the enzyme kinetic parameters [37] , [38] , [39] . The above assay reveals that 1a inhibit M pro in a time-dependent pattern, and the kinetic progression curves exhibited a biphasic character ( Fig.…”

“…The inhibition mode of hydroxamate 1a on M pro was evaluated and the kinetic parameters were determined [37] , [38] . In detail, the substrate (20 μM) was added into assay buffer supplement with 1a at different concentrations (1-30 μM), respectively.…”

Pyridine-2,6-Dithiocarboxylic Acid and Its Metal Complexes: New Inhibitors of New Delhi Metallo -Lactamase-1

“…During our investigations of transition metal drugs and metal complexes for new inhibitors of NDM-1 and other MBLs, Chen and colleagues identified cisplatin and Pd complexes as potent inhibitors of MBL activity [ 49 ]. From their data, they posit that the metal or ligand-bound metal species replaces one of the zinc ions in the active site.…”

Discovery of a Novel Natural Allosteric Inhibitor That Targets NDM-1 Against Escherichia coli

“…In addition, Chen Cheng et al found that disulfiram is a promising candidate for the development of NDM-1 inhibitors, which can covalently bind to NDM-1 by forming an S–S bond with Cys208 residue at the active site ( Chen et al, 2020b ). At the same time, some metal complexes (cisplatin and Palladium(II) complexes) ( Chen et al, 2020a ) and DNA aptamers ( Khan et al, 2019 ) have also been found to have inhibitory effects on NDM-1. Among them, the metal complexes inhibited MβLs through a new inhibition mode, which binds to the Cys208 residue in the active site, causing Zn 2+ to be replaced by other ions.…”