Mercaptopyrimidine-Conjugated Gold Nanoclusters as Nanoantibiotics for Combating Multidrug-Resistant Superbugs

Abstract

Widespread bacterial resistance induced by the abuse of antibiotics eagerly needs the exploitation of novel antimicrobial agents and strategies. Gold nanoclusters (Au NCs) have recently emerged as an innovative nanomedicine, but study on their antibacterial properties especially toward multidrug resistant (MDR) bacteria is scarce. Herein, we demonstrate that a novel class of Au NCs, mercaptopyrimidine conjugated Au NCs, can act as potent nanoantibiotics targeting these intractable superbugs in vitro and in vivo, without induction of bacterial antibiotic resistance and noticeable cytotoxicity to mammalian cells. The Au NCs kill these superbugs through a combined mechanism including cell membrane destruction, DNA damage, and reactive oxygen species (ROS) generation, and exhibit excellent treatment effects in both macrophages and animal infection models induced by methicillin-resistant Staphylococcus aureus as representative. Moreover, the induction of intracellular ROS production in bacterial cells mainly attributed to the Au NCs' intrinsic oxidase- and peroxidase-like catalytic activities has been demonstrated for the first time.

Gold Nanoclusters for Bacterial Detection and Infection Therapy

“…The total antibacterial activity is mainly attributed to the synergistic effect of SFT and NDs on the disruption of the bacterial cell membrane. In our recent study, we developed an effective antibacterial hybrid (Dap-Au NCs) by incorporating antimicrobial peptide (daptomycin, Dap) and antibacterial Au NCs (Zheng et al, 2018c;. The antibacterial hybrid could high-efficiently damage bacterial cell membrane because Dap moiety may induce the creation of holes on the cell membranes, and motivate the entry of Dap-Au NCs inside bacteria and even lead to serious DNA destruction (Figure 7A).…”

“…Similar circumstances have been witnessed in our recent work. We demonstrated that mercaptopyrimidine analogs templated Au NCs can serve as potent nanoantibiotics for ESKAPE superbugs (Zheng et al, 2018c). Mercaptopyrimidine analogs, including 4,6-dihydroxyl-2-mercaptopyrimidine (DHMP), 4-amino-6-hydroxyl-2-mercaptopyrimidine (AHMP), 4,6-diamino-2-mercaptopyrimidine (DAMP), and 4-amino-2-mercaptopyrimidine (AMP), were employed as templates and reducing agents to prepare Au NCs.…”

“…In addition to size effects, the surface ligand chemistry of Au NCs also profoundly affects their antibacterial properties. In general, antibacterial agents with positive surface charges are considered to lead higher antibacterial abilities (El Badawy et al, 2011;Le Ouay and Stellacci, 2015;Zheng et al, 2018c). However, Zheng et al obtained the opposite results when using Au 25 (SR) 18 NCs (SR means thiolate ligands) (Zheng et al, 2018a).…”

Advances in the Experimental and Theoretical Understandings of Antibiotic Conjugated Gold Nanoparticles for Antibacterial Applications

“…Generally, AuNPs do not exhibit antibacterial property, but due to the presence of unreacted ligands or some ionic impurities, they act as an antibacterial agent . AuNPs can be made antibacterial by grafting hydrophobic molecules, antibacterial peptides, antibiotics and a molecule which makes the gold nanoparticles positively charged . Most often, antibiotic molecules have been used to make the AuNPs antibacterial in nature .…”

Coupling Biocompatible Au Nanoclusters and Cellulose Nanofibrils to Prepare the Antibacterial Nanocomposite Films

“…Thus, 4, 6-diamino-2-mercaptopyrimidine (DAMP), an analog of 2-mercaptopyrimidine in the tRNA of E. coli, has been employed as the surface ligand to functionalize AuNCs. The DAMP-capped AuNCs show a robust capacity to eliminate bacteria through DNA destruction, membrane damage, and ROS production (Zheng et al, 2018). Importantly, the AuNCs have great biocompatibility and antibacterial efficiency, indicating that they are suitable for clinical infection therapy.…”