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In Vitro and In Vivo Development of a β-Lactam-Metallo-β-Lactamase Inhibitor: Targeting Carbapenem-Resistant Enterobacterales.
| Content Provider | Europe PMC |
|---|---|
| Author | Peters, ByronK. Reddy, Nakita Shungube, Mbongeni Girdhari, Letisha Baijnath, Sooraj Mdanda, Sipho Chetty, Lloyd Ntombela, Thandokuhle Arumugam, Thilona Bester, Linda A. Singh, Sanil D. Chuturgoon, Anil Arvidsson, Per I. Maguire, Glenn E. M. Kruger, Hendrik G. Naicker, Tricia Govender, Thavendran |
| Copyright Year | 2023 |
| Abstract | β-lactams are the most prescribed class of antibioticsdueto their potent, broad-spectrum antimicrobial activities. However,alarming rates of antimicrobial resistance now threaten the clinicalrelevance of these drugs, especially for the carbapenem-resistant Enterobacterales expressing metallo-β-lactamases(MBLs). Antimicrobial agents that specifically target these enzymesto restore the efficacy of last resort β-lactam drugs, thatis, carbapenems, are therefore desperately needed. Herein, we presenta cyclic zinc chelator covalently attached to a β-lactam scaffold(cephalosporin), that is, BP1. Observations from in vitro assays (withseven MBL expressing bacteria from different geographies) have indicatedthat 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 (IC50 > 1000 mg/L) and exhibited a potency of (Kiapp) 24.8 and 97.4 μM against Verona integron-encodedMBL (VIM-2) and New Delhi metallo β-lactamase (NDM-1), respectively.There was no inhibition observed from BP1 with the human zinc-containingenzyme glyoxylase II up to 500 μM. Preliminary molecular dockingof BP1 with NDM-1 and VIM-2 sheds light on BP1’s mode of action.In Klebsiella pneumoniae NDM infectedmice, BP1 coadministered with meropenem was efficacious in reducingthe bacterial load by >3 log10 units’ postinfection.The findings herein propose a favorable therapeutic combination strategythat restores the activity of the carbapenem antibiotic class andcomplements the few MBL inhibitors under development, with the ultimategoal of curbing antimicrobial resistance. |
| Related Links | https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC10012271&blobtype=pdf |
| Journal | ACS Infectious Diseases [ACS Infect Dis] |
| Volume Number | 9 |
| DOI | 10.1021/acsinfecdis.2c00485 |
| PubMed Central reference number | PMC10012271 |
| Issue Number | 3 |
| PubMed reference number | 36786013 |
| e-ISSN | 23738227 |
| Language | English |
| Publisher | American Chemical Society |
| Publisher Date | 2023-02-14 |
| Access Restriction | Open |
| Rights License | Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/). © 2023 American Chemical Society |
| Subject Keyword | β-Lactam-Metallo-β-Lactamase Inhibitor carbapenem-resistant Enterobacterales human hepatocarcinomacells Verona integron-encoded MBL New Delhi metalloβ-lactamase Klebsiella pneumoniae |
| Content Type | Text |
| Resource Type | Article |
| Subject | Infectious Diseases |
