Aminotetrazole-Gold Nanocomplexes Shunt Electrons to Eradicate Bacteria Without ROS-Induced Resistance.

Abstract

Most bactericides directly or indirectly disrupt the electron transport chain (ETC)-mediated energy metabolism to exert antibacterial effects. However, the consequent perturbation of electron transfer states (e.g., flux overload or blockade) leads to electron accumulation, which enhances reactive oxygen species (ROS) generation. High ROS concentrations kill bacteria, while sublethal levels induce DNA damage, thereby elevating antibiotic resistance risk. In this study, we found that shunting electrons at critical ETC nodes is able to disrupt bacterial energy metabolism, damaging bacteria without ROS generation. To leverage the ROS-free mechanism for infection control, we synthesized 5-aminotetrazole-functionalized gold nanocomplexes (ATZ-Au) that intercept electron transfer from electron donors to downstream carriers. This rapidly depletes reduced nicotinamide adenine dinucleotide (NADH), disrupts the proton motive force (PMF), impairs ATP synthesis, and blocks bacterial compensatory metabolic pathways, ultimately leading to lethal intracellular acidosis and metabolic collapse. This effect blocks the capture of electrons by oxygen, thereby preventing the generation of ROS. The ATZ-Au efficiently eliminates pathogenic bacteria in complex infections, providing a promising strategy to address antibiotic resistance.