Authors
Xiaodan Li, Ziyi Zhang, Zhaoran Zhang, Di Liu, Hao Lu, Wenjia Lu, Yulin Qian, Huanchun Chen, Chenchen Wang, Chen Tan
Published in
Virulence. Volume 17. Issue 1. Pages 2728436. Epub Sep 08, 2026.
Abstract
The widespread dissemination of New Delhi metallo-β-lactamase-1 (NDM-1) has severely compromised the clinical efficacy of carbapenem antibiotics, highlighting the need for strategies to restore meropenem activity. SKQ1 was identified through surface plasmon resonance (SPR)-based screening. Broth microdilution checkerboard assays demonstrated strong synergy between SKQ1 and meropenem (FICI = 0.25-0.5). Enzyme kinetic analyses revealed that SKQ1 acts as a noncompetitive inhibitor of NDM-1 (IC50 = 34.99 ± 3.13 μg/mL). Molecular docking, molecular dynamics simulations, microscale thermophoresis (MST) and thermal stability assays collectively supported the direct binding of SKQ1 to NDM-1, resulting in the inhibition of its hydrolytic activity. Further analyses showed that SKQ1 affected bacterial envelope physiology, including membrane integrity, membrane potential, ATP distribution and oxidative stress, suggesting additional envelope-associated effects beyond NDM-1 inhibition. Both in vitro and in vivo models confirmed the efficacy of the SKQ1-meropenem combination. SKQ1 enhanced the antibiofilm activity and therapeutic efficacy of meropenem while attenuating lipopolysaccharide (LPS)-induced inflammatory responses. Together, these findings support SKQ1 as a repurposed meropenem potentiator that acts through NDM-1 inhibition and envelope-associated effects, offering a potential strategy for combating NDM-mediated carbapenem resistance.
PMID:
42711660
Bibliographic data and abstract were imported from PubMed on 09 Sep 2026.
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