» Articles » PMID: 36786013

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

Abstract

β-lactams are the most prescribed class of antibiotics due to their potent, broad-spectrum antimicrobial activities. However, alarming rates of antimicrobial resistance now threaten the clinical relevance of these drugs, especially for the carbapenem-resistant expressing metallo-β-lactamases (MBLs). Antimicrobial agents that specifically target these enzymes to restore the efficacy of last resort β-lactam drugs, that is, carbapenems, are therefore desperately needed. Herein, we present a cyclic zinc chelator covalently attached to a β-lactam scaffold (cephalosporin), that is, BP1. Observations from in vitro assays (with seven MBL expressing bacteria from different geographies) have indicated that BP1 restored the efficacy of meropenem to ≤ 0.5 mg/L, with sterilizing activity occurring from 8 h postinoculation. Furthermore, BP1 was nontoxic against human hepatocarcinoma cells (IC > 1000 mg/L) and exhibited a potency of (K) 24.8 and 97.4 μM against Verona integron-encoded MBL (VIM-2) and New Delhi metallo β-lactamase (NDM-1), respectively. There was no inhibition observed from BP1 with the human zinc-containing enzyme glyoxylase II up to 500 μM. Preliminary molecular docking of BP1 with NDM-1 and VIM-2 sheds light on BP1's mode of action. In NDM infected mice, BP1 coadministered with meropenem was efficacious in reducing the bacterial load by >3 log units' postinfection. The findings herein propose a favorable therapeutic combination strategy that restores the activity of the carbapenem antibiotic class and complements the few MBL inhibitors under development, with the ultimate goal of curbing antimicrobial resistance.

Citing Articles

Approachable Synthetic Methodologies for Second-Generation -Lactamase Inhibitors: A Review.

Fatima N, Khalid S, Rasool N, Imran M, Parveen B, Kanwal A Pharmaceuticals (Basel). 2024; 17(9).

PMID: 39338273 PMC: 11434895. DOI: 10.3390/ph17091108.


Synthesis and biological evaluation of novel β-lactam-metallo β-lactamase inhibitors.

Shungube M, Hlophe A, Girdhari L, Sabe V, Peters B, Reddy N RSC Adv. 2023; 13(28):18991-19001.

PMID: 37362332 PMC: 10285615. DOI: 10.1039/d3ra02490c.


Neutralizing Carbapenem Resistance by Co-Administering Meropenem with Novel β-Lactam-Metallo-β-Lactamase Inhibitors.

Reddy N, Girdhari L, Shungube M, Gouws A, Peters B, Rajbongshi K Antibiotics (Basel). 2023; 12(4).

PMID: 37106995 PMC: 10135050. DOI: 10.3390/antibiotics12040633.

References
1.
Harada R, Kitao A . Parallel Cascade Selection Molecular Dynamics (PaCS-MD) to generate conformational transition pathway. J Chem Phys. 2013; 139(3):035103. DOI: 10.1063/1.4813023. View

2.
Thomas C, Cheng Z, Yang K, Hellwarth E, Yurkiewicz C, Baxter F . Probing the mechanisms of inhibition for various inhibitors of metallo-β-lactamases VIM-2 and NDM-1. J Inorg Biochem. 2020; 210:111123. DOI: 10.1016/j.jinorgbio.2020.111123. View

3.
Omolabi K, Reddy N, Mdanda S, Ntshangase S, Singh S, Kruger H . The in vitro and in vivo potential of metal-chelating agents as metallo-beta-lactamase inhibitors against carbapenem-resistant Enterobacterales. FEMS Microbiol Lett. 2022; 370. DOI: 10.1093/femsle/fnac122. View

4.
Lomovskaya O, Nelson K, Rubio-Aparicio D, Tsivkovski R, Sun D, Dudley M . Impact of Intrinsic Resistance Mechanisms on Potency of QPX7728, a New Ultrabroad-Spectrum Beta-Lactamase Inhibitor of Serine and Metallo-Beta-Lactamases in , Pseudomonas aeruginosa, and Acinetobacter baumannii. Antimicrob Agents Chemother. 2020; 64(6). PMC: 7269478. DOI: 10.1128/AAC.00552-20. View

5.
Mallalieu N, Winter E, Fettner S, Patel K, Zwanziger E, Attley G . Safety and Pharmacokinetic Characterization of Nacubactam, a Novel β-Lactamase Inhibitor, Alone and in Combination with Meropenem, in Healthy Volunteers. Antimicrob Agents Chemother. 2020; 64(5). PMC: 7179653. DOI: 10.1128/AAC.02229-19. View