Targeting Achilles’ Heel: Copper-Based Nanoantibiotics Synergistically Disrupt the TCA Cycle to Induce Bacterial Metabolic Cell Death

Central carbon metabolism is essential for bacterial survival, making it a promising target for antimicrobial strategies. Bacterial cuproptosis-like and ferroptosis-like deaths are tightly linked to central carbon metabolism, yet their complete mechanistic cascades remain poorly understood. In addition, both death pathways are constrained by intracellular glutathione (GSH). Herein, we constructed chitosan-copper nanoclusters (CS-CuCs) as nanoantibiotics that selectively accumulate within bacteria to synergistically disrupt the tricarboxylic acid (TCA) cycle. CS-CuCs induces copper overload, impairs lipoylated and iron-sulfur (Fe-S) proteins, triggering cuproptosis-like death. Their peroxidase-like activity further generates reactive oxygen species, thereby exacerbating TCA cycle disruption. The subsequent dysfunction in central carbon metabolism reduces the supply of biosynthetic precursors of GSH, thereby compromising antioxidant defenses and provoking ferroptosis-like death. Metabolic collapse ultimately leads to cascading metabolic cell death in bacteria. Notably, CS-CuCs effectively eradicate biofilm-embedded and multidrug-resistant bacteria and exhibit excellent therapeutic efficacy in a mouse peritonitis-sepsis infection model. This study establishes a central carbon metabolism-targeted metabolic disruption strategy, providing a novel paradigm for triggering bacterial metabolic cell death.