Conjugating gold nanoclusters and antimicrobial peptides: From aggregation-induced emission to antibacterial synergy

Antimicrobial peptides and antibacterial nanostructures are two emerging classes of antimicrobial agents that differ from conventional small-molecule antibiotics. Combining these two types of antimicrobial agents into one entity may be an effective strategy to improve their antimicrobial efficiency. In this study, we demonstrated an effective antibacterial hybrid formed by covalently conjugating antibacterial gold nanoclusters (Au NCs, a novel antimicrobial nanostructure) and daptomycin (Dap, a cyclic lipopeptide antimicrobial peptide). The as-synthesized hybrid structure (Dap-Au NCs) not only inherits the intrinsic properties from both agents but also renders an enhanced synergistic effect. Compared with the physically mixed Au NCs and daptomycin (Dap+Au NCs), the Dap-Au NCs hybrid structure has a stronger bactericidal effect toward methicillin-resistant Staphylococcus aureus, a representative of multidrug-resistant bacteria. Dap-Au NCs could effectively disrupt bacterial membranes by creating more and/or larger holes in the membranes due to the localized daptomycin within the conjugated structure. These larger (and possibly more) holes motivate the entry of Dap-Au NCs into bacterial cells and lead to more serious damage of the bacteria at subcellular levels. Moreover, bacterial genomic DNA fragmentation was further quantified to show that Dap-Au NCs may induce severe DNA breaks. The strong DNA destruction benefited from localized high concentrations of reactive oxygen species (ROS) induced by the localization of Au NCs in the antimicrobial conjugation. The conjugated Au NCs could serve as a critical free radical generator to continuously produce ROS within the bacteria. The continuous ROS bombings also limit the capacity of the bacteria to develop drug resistance. In addition, a significant fluorescence enhancement of the hybrid structure was observed due to a novel aggregation-induced emission (AIE) pattern caused by the Au NCs and daptomycin conjugation. This conjugation strategy provides a new perspective for the synthesis of new antimicrobial agents as well as AIE-type fluorescence materials.