Novel metallo-β-lactamases inhibitors restore the susceptibility of carbapenems to New Delhi metallo-lactamase-1 (NDM-1)-harbouring bacteria.

Publisher: Wiley Country of Publication: England NLM ID: 7502536 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5381 (Electronic) Linking ISSN: 00071188 NLM ISO Abbreviation: Br J Pharmacol Subsets: MEDLINE

Publication: London : Wiley
Original Publication: London, Macmillian Journals Ltd.

Carbapenems*/pharmacology ; Carbapenems*/chemistry ; Dexrazoxane*; Animals ; Mice ; Meropenem/pharmacology ; beta-Lactamase Inhibitors/pharmacology ; Masoprocol ; Anti-Bacterial Agents/pharmacology ; beta-Lactamases/metabolism ; Bacteria/metabolism ; Microbial Sensitivity Tests

Background and Purpose: The production of metallo-β-lactamases is a major mechanisms adopted by bacterial pathogens to resist carbapenems. Repurposing approved drugs to restore the efficacy of carbapenems represents an efficient and cost-effective approach to fight infections caused by carbapenem resistant pathogens.
Experimental Approach: The nitrocefin hydrolysis assay was employed to screen potential New Delhi metallo-lactamase-1 (NDM-1) inhibitors from a commercially available U.S. Food and Drug Administration (FDA) approved drug library. The mechanism of inhibition was clarified by metal restoration, inductively coupled plasma mass spectrometry (ICP-MS) and molecular dynamics simulation. The in vitro synergistic antibacterial effect of the identified inhibitors with meropenem was determined by the checkerboard minimum inhibitory concentration (MIC) assay, time-dependent killing assay and combined disc test. Three mouse infection models were used to further evaluate the in vivo therapeutic efficacy of combined therapy.
Key Results: Twelve FDA-approved compounds were initially screened to inhibit the ability of NDM-1 to hydrolyse nitrocefin. Among these compounds, dexrazoxane, embelin, candesartan cilexetil and nordihydroguaiaretic acid were demonstrated to inhibit all tested metallo-β-lactamases and showed an in vitro synergistic bactericidal effect with meropenem against metallo-β-lactamases-producing bacteria. Dexrazoxane, embelin and candesartan cilexetil are metal ion chelating agents, while the inhibition of NDM-1 by nordihydroguaiaretic acid involves its direct binding to the active region of NDM-1. Furthermore, these four drugs dramatically rescued the treatment efficacy of meropenem in three infection models.
Conclusions and Implications: Our observations indicated that dexrazoxane, embelin, candesartan cilexetil and nordihydroguaiaretic acid are promising carbapenem adjuvants against metallo-β-lactamases-positive carbapenem resistant bacterial pathogens.
(© 2023 British Pharmacological Society.)

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2021YFD1801000 National Key Research and Development Program of China; 32172912 National Natural Science Foundation of China; 81861138046 National Natural Science Foundation of China; JLUXKJC2021QZ04 Interdisciplinary Integration and Innovation Project of JLU; Fundamental Research Funds for the Central Universities

Keywords: FDA-approved drug library; carbapenem-resistant gram-negative bacteria; carbapenems; drug repurposing; metallo-β-lactamase

0 (Carbapenems)
FV9J3JU8B1 (Meropenem)
EWP54G0J8F (nitrocefin)
EC 3.5.2.6 (beta-lactamase NDM-1)
R85M2X0D68 (candesartan cilexetil)
SHC6U8F5ER (embelin)
0 (beta-Lactamase Inhibitors)
7BO8G1BYQU (Masoprocol)
048L81261F (Dexrazoxane)
0 (Anti-Bacterial Agents)
EC 3.5.2.6 (beta-Lactamases)

Date Created: 20230804 Date Completed: 20231206 Latest Revision: 20240306

20250114

10.1111/bph.16210

37539785