Responsive Assembly of Silver Nanoclusters with a Biofilm Locally Amplified Bactericidal Effect to Enhance Treatments against Multi-Drug-Resistant Bacterial Infections

Abstract

Bacterial biofilms pose a major threat to public health because they are resistant to most current therapeutics. Conventional antibiotics exhibit limited penetration and weakened activity in the acidic microenvironment of a biofilm. Here, the development of biofilm-responsive nanoantibiotics (rAgNAs) composed of self-assembled silver nanoclusters and pH-sensitive charge reversal ligands, whose bactericidal activity can be selectively boosted in the biofilm microenvironment, is reported. Under neutral physiological conditions, the bactericidal activity of rAgNAs is self-quenched because the toxic silver ions’ release is largely inhibited; however, upon entry into the acidic biofilm microenvironment, the rAgNAs not only exhibit charge reversal to facilitate local accumulation and retention but also disassemble into small silver nanoclusters, thus enabling deep penetration and accelerated silver ions release for dramatically amplified bactericidal activity. The superior antibiofilm activity of rAgNAs is demonstrated both in vitro and in vivo, and the mortality rate of mice with multi-drug-resistant biofilm-induced severe pyomyositis can be significantly reduced by rAgNAs treatment, indicating the immense potential of rAgNAs as highly efficient nanoscale antibacterial agents to combat resistant bacterial biofilm-associated infections.

Interactions of Gold and Silver Nanoparticles with Bacterial Biofilms: Molecular Interactions behind Inhibition and Resistance

“…The pH of the biofilm microenvironment also governs its interactions with nanoparticles. For example, Hu et al and Wu et al have shown improved interactions and penetration of AuNPs and AgNPs in methicillin-resistant S. aureus biofilm [ 78 , 79 ]. Hu et al used 11-mercaptodecanoic acid and (10-mercaptodecyl)-trimethylammonium bromide coated AuNPs and showed that due to the zwitterionic nature of ligands on the surface of nanoparticles, Van der Waals attraction, hydrogen-bonding, hydration repulsion and electrostatic repulsion remained balanced, keeping nanoparticles stably dispersed at neutral pH.…”

“…However, upon entering the acidic microenvironment of the biofilm, the ligands underwent charge reversal, leading to improved electrostatic repulsion and disassembly of silver nanoclusters and reduction in nanoparticle size (from ~150 nm to ~8 nm). This reduction greatly accelerated the dissolution of nanoparticles and silver ion leaching, which eventually eradicated the methicillin-resistant S. aureus biofilm [ 79 ]. These reports prove that biofilm pH has a significant impact on its interaction with metallic nanoparticles [ 78 , 79 ].…”

“…This reduction greatly accelerated the dissolution of nanoparticles and silver ion leaching, which eventually eradicated the methicillin-resistant S. aureus biofilm [ 79 ]. These reports prove that biofilm pH has a significant impact on its interaction with metallic nanoparticles [ 78 , 79 ]. Biofilm surface chemistry is another factor that could alter the course of biofilm–nanoparticle interactions.…”

Towards Robust Delivery of Antimicrobial Peptides to Combat Bacterial Resistance

“…Firstly, pH-sensitive linkers can take advantage of the local low pH environment associated with bacterial infection and biofilms. This pH can reach as low as 4.5 in the case of biofilms [42][43][44] and is associated with anaerobic fermentation and inflammation, both of which produce acidic products [41,42]. Targeting infection-associated pH allows for indiscriminate bacterial targeting, which can be useful in broad-spectrum targeting.…”

Lipid-Based Antimicrobial Delivery-Systems for the Treatment of Bacterial Infections

“…This renders stealth properties to the micelles at physiological pH due to the exposure of the PEG-shell allowing their presence in the blood circulation without negative side-effects and penetration in a tumor or infectious biofilm. However, once in a more acidic, pathological site, such as in a tumor (Ray et al, 2019) or biofilm (Liu et al, 2016;Wu et al, 2019) (becoming even more acidic toward its bottom; Peeridogaheh et al, 2019), pH-responsive PAE groups become positively-charged causing self-targeting and accumulation (Liu et al, 2012(Liu et al, , 2016. Micelles are more suitable for functionalizing of their surface without affecting their hydrophilicity ratio than liposomes, FIGURE 1 | Nanotechnology-derived antimicrobial delivery-systems, including nanofiber-composed hydrogels.…”