Repurposing SKQ1 as a meropenem potentiator against NDM-1-producing Escherichia coli

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.