Pathogen-targeting bismuth nanocluster via photothermally-mediated NDM-1 inactivation and bacterial membrane destabilization combat NDM-1-producing bacteria

Abstract

New Delhi metallo-β-lactamase-1 (NDM-1) is the most prevalent type of metallo-β-lactamase and hydrolyzes almost all clinically used β-lactam antibiotics, including last line antibiotic - carbapenems. Inactivating NDM-1 and then reviving carbapenems holds great promise in treating NDM-1-producing bacteria, while better intracellular antibiotic accumulation and precise NDM-1 inactivation are challenges. Herein, a photothermal-assisted biomimetic antibiotic booster (PBM) is engineered for repurposing carbapenems against NDM-1-producing bacteria by photothermal-induced bacterial membrane destabilizing and synchronous NDM-1 inactivation. In the PBM nanomedicine, stomach medicine-converted bismuth nanoclusters (BiNCs) with excellent photothermal effect are used as photothermal skeleton, loading meropenem (MEM) on the inside and coating platelet membrane vesicles (PMVs) on the outside. Due to the inherent inflammatory properties of platelets, PBM exhibits an excellent homing effect on infectious sites and precise homologous targeting of pathogens. Meanwhile, due to the excellent photothermal properties of bismuth nanoclusters, PBM enhanced the intracellular accumulation of meropenem via breaking the bacterial outer membrane barrier, and then effectively inactivated NDM-1. Benefiting from the combination of photothermal-assisted bacterial membrane destabilizing and NDM-1 inactivation, PBM (100 μg/mL) effectively reversed the resistance of NDM-1-producing Escherichia coli to meropenem, exhibiting a more significant antibacterial effect (sterilization rate reached 98.9 %) than equivalent meropenem alone by time-killing curve.