A potential strategy against clinical carbapenem-resistant Enterobacteriaceae: antimicrobial activity study of sweetener-decorated gold nanoparticles in vitro and in vivo

Abstract

Background Carbapenem-resistant Enterobacteriaceae (CRE) present substantial challenges to clinical intervention, necessitating the formulation of novel antimicrobial strategies to counteract them. Nanomaterials offer a distinctive avenue for eradicating bacteria by employing mechanisms divergent from traditional antibiotic resistance pathways and exhibiting reduced susceptibility to drug resistance development. Non-caloric artificial sweeteners, commonly utilized in the food sector, such as saccharin, sucralose, acesulfame, and aspartame, possess structures amenable to nanomaterial formation. In this investigation, we synthesized gold nanoparticles decorated with non-caloric artificial sweeteners and evaluated their antimicrobial efficacy against clinical CRE strains. Results Among these, gold nanoparticles decorated with aspartame (ASP_Au NPs) exhibited the most potent antimicrobial effect, displaying minimum inhibitory concentrations ranging from 4 to 16 µg/mL. As a result, ASP_Au NPs were chosen for further experimentation. Elucidation of the antimicrobial mechanism unveiled that ASP_Au NPs substantially elevated bacterial reactive oxygen species (ROS) levels, which dissipated upon ROS scavenger treatment, indicating ROS accumulation within bacteria as the fundamental antimicrobial modality. Furthermore, findings from membrane permeability assessments suggested that ASP_Au NPs may represent a secondary antimicrobial modality via enhancing inner membrane permeability. In addition, experiments involving crystal violet and confocal live/dead staining demonstrated effective suppression of bacterial biofilm formation by ASP_Au NPs. Moreover, ASP_Au NPs demonstrated notable efficacy in the treatment of Galleria mellonella bacterial infection and acute abdominal infection in mice, concurrently mitigating the organism's inflammatory response. Crucially, evaluation of in vivo safety and biocompatibility established that ASP_Au NPs exhibited negligible toxicity at bactericidal concentrations. Conclusions Our results demonstrated that ASP_Au NPs exhibit promise as innovative antimicrobial agents against clinical CRE. Graphical Abstract

Synergistic activity of gold nanoparticles with amphotericin B on persister cells of Candida tropicalis biofilms

“…The search to find new antimicrobials for the prevention and treatment of Candida biofilm-associated infections has been gaining greater interest, with an increasing investigation into newer methods including novel nanotechnology-based approaches [ 16 , 18 , 40 ]. Although metal NPs have demonstrated a remarkable potential against bacterial infections, they have limited use in the treatment of fungal infections and have not been shown to be useful in new approaches to eradicate PCs within biofilms [ 19 , 20 , 41 – 43 ].…”

Alteration of oral microbial biofilms by sweeteners

“…Nanoparticles can easily interact with microorganisms owing to their small sizes and high surface-area-to-volume ratios [ 96 , 97 ]. In addition, they can also serve as carriers of antibacterial agents for drug administration [ 39 , 98 ]. Nanoparticles loaded with sweeteners have been developed to improve biofilm penetration of xylitol [ 37 ].…”

“…PLGA nanoparticles containing xylitol showed high levels of biofilm activity by enhancing the penetration of S. aureus and P. aeruginosa biofilms into EPS. In a study synthesizing non-nutritive decorated gold nanoparticles, aspartame-decorated gold nanoparticles showed stronger antibacterial and antibiofilm effects against Carbapenem-resistant Enterobacteriaceae than gold nanoparticles decorated with saccharin, sucralose, and acesulfame [ 39 ]. Gold nanoparticles decorated with aspartame showed an antibacterial effect by accumulating reactive oxygen species in bacteria and improving internal membrane permeability.…”

“…These sweeteners have also been used in conjunction with antimicrobial substances to inhibit biofilm formation [ [34] , [35] , [36] ]. Formulations with bulk and non-nutritive sweeteners have been described to efficiently reduce biofilm-forming microbial pathogens [ [37] , [38] , [39] ].…”