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Metallo-?-Lactamase Inhibitors Inspired on Snapshots from the Catalytic Mechanism.

ABSTRACT: ?-Lactam antibiotics are the most widely prescribed antibacterial drugs due to their low toxicity and broad spectrum. Their action is counteracted by different resistance mechanisms developed by bacteria. Among them, the most common strategy is the expression of ?-lactamases, enzymes that hydrolyze the amide bond present in all ?-lactam compounds. There are several inhibitors against serine-?-lactamases (SBLs). Metallo-?-lactamases (MBLs) are Zn(II)-dependent enzymes able to hydrolyze most ?-lactam antibiotics, and no clinically useful inhibitors against them have yet been approved. Despite their large structural diversity, MBLs have a common catalytic mechanism with similar reaction species. Here, we describe a number of MBL inhibitors that mimic different species formed during the hydrolysis process: substrate, transition state, intermediate, or product. Recent advances in the development of boron-based and thiol-based inhibitors are discussed in the light of the mechanism of MBLs. We also discuss the use of chelators as a possible strategy, since Zn(II) ions are essential for substrate binding and catalysis.

SUBMITTER: Palacios AR

PROVIDER: S-EPMC7356002 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Metallo-β-Lactamase Inhibitors Inspired on Snapshots from the Catalytic Mechanism.

Palacios Antonella R AR Rossi María-Agustina MA Mahler Graciela S GS Vila Alejandro J AJ

Biomolecules 20200603 6

β-Lactam antibiotics are the most widely prescribed antibacterial drugs due to their low toxicity and broad spectrum. Their action is counteracted by different resistance mechanisms developed by bacteria. Among them, the most common strategy is the expression of β-lactamases, enzymes that hydrolyze the amide bond present in all β-lactam compounds. There are several inhibitors against serine-β-lactamases (SBLs). Metallo-β-lactamases (MBLs) are Zn(II)-dependent enzymes able to hydrolyze most β-lac ...[more]

PMID: 32503337

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Project description:Metallo-?-lactamase (MBL)-producing Enterobacteriaceae are of grave clinical concern, particularly as there are no metallo-?-lactamase inhibitors approved for clinical use. The discovery and development of MBL inhibitors to restore the efficacy of available ?-lactams are thus imperative. We investigated a zinc-chelating moiety, 1,4,7-triazacyclononane (TACN), for its inhibitory activity against clinical carbapenem-resistant Enterobacteriaceae MICs, minimum bactericidal concentrations (MBCs), the serum effect, fractional inhibitory concentration indexes, and time-kill kinetics were determined using broth microdilution techniques according to Clinical and Laboratory Standards Institute (CSLI) guidelines. Enzyme kinetic parameters and the cytotoxic effects of TACN were determined using spectrophotometric assays. The interactions of the enzyme-TACN complex were investigated by computational studies. Meropenem regained its activity against carbapenemase-producing Enterobacteriaceae, with the MIC decreasing from between 8 and 64?mg/liter to 0.03?mg/liter in the presence of TACN. The TACN-meropenem combination showed bactericidal effects with an MBC/MIC ratio of ?4, and synergistic activity was observed. Human serum effects on the MICs were insignificant, and TACN was found to be noncytotoxic at concentrations above the MIC values. Computational studies predicted that TACN inhibits MBLs by targeting their catalytic active-site pockets. This was supported by its inhibition constant (Ki ), which was 0.044??M, and its inactivation constant (K inact), which was 0.0406 min-1, demonstrating that TACN inhibits MBLs efficiently and holds promise as a potential inhibitor.IMPORTANCE Carbapenem-resistant Enterobacteriaceae (CRE)-mediated infections remain a significant public health concern and have been reported to be critical in the World Health Organization's priority pathogens list for the research and development of new antibiotics. CRE produce enzymes, such as metallo-?-lactamases (MBLs), which inactivate ?-lactam antibiotics. Combination therapies involving a ?-lactam antibiotic and a ?-lactamase inhibitor remain a major treatment option for infections caused by ?-lactamase-producing organisms. Currently, no MBL inhibitor-?-lactam combination therapy is clinically available for MBL-positive bacterial infections. Hence, developing efficient molecules capable of inhibiting these enzymes could be a promising way to overcome this phenomenon. TACN played a significant role in the inhibitory activity of the tested molecules against CREs by potentiating the activity of carbapenem. This study demonstrates that TACN inhibits MBLs efficiently and holds promises as a potential MBL inhibitor to help curb the global health threat posed by MBL-producing CREs.

Dataset Information

Metallo-?-Lactamase Inhibitors Inspired on Snapshots from the Catalytic Mechanism.

Publications

Metallo-β-Lactamase Inhibitors Inspired on Snapshots from the Catalytic Mechanism.

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