Amphiphilic silver nanoclusters show active nano–bio interaction with compelling antibacterial activity against multidrug-resistant bacteria

Multidrug resistance represents a growing threat to human beings, and alternative antimicrobial regimens to conventional antibiotic paradigms are being extensively searched to fight against multidrug-resistant bacteria (MDRB). Although the antimicrobial potency of silver nanomaterials (AgNMs) has been previously elaborated, their efficacy against MDRB still remains to be strengthened. Here, our data revealed that small-sized silver nanoclusters (AgNCs) are superior to conventional silver nanoparticles (AgNPs) as robust antimicrobials against multidrug-resistant (MDR) Pseudomonas aeruginosa (P. aeruginosa). The core structure and surface ligands of AgNCs are crucial for the outstanding antibacterial activity of AgNCs. On the one hand, due to the presence of amphiphilic ligands, AgNCs are relatively prone to associate with the cell membrane and partake in endocytosis with targeted bacterial cells. Molecular dynamics simulations also corroborated this finding. On the other hand, the nanocluster structure of AgNCs led to strong peroxide-like activity associated with massive production of reactive oxygen species (ROS), which contributes to their overall bactericidal potency. These sustaining features of AgNCs result in elevated bacterial killing efficacy by impairing the cell membrane, promoting oxidative stress and attenuating pivotal cellular processes, e.g., ATP synthesis. Notably, AgNCs manifested great efficacy against P. aeruginosa-generated pneumonia in mice and increased the survival of treated animals, as well as exhibited excellent biocompatibility. Taken together, the results of this study pinpoint the great promise of AgNCs as new alternative therapeutics against MDR P. aeruginosa.