Ag-Based Synergistic Antimicrobial Composites. A Critical Review

Abstract

The emerging problem of the antibiotic resistance development and the consequences that the health, food and other sectors face stimulate researchers to find safe and effective alternative methods to fight antimicrobial resistance (AMR) and biofilm formation. One of the most promising and efficient groups of materials known for robust antimicrobial performance is noble metal nanoparticles. Notably, silver nanoparticles (AgNPs) have been already widely investigated and applied as antimicrobial agents. However, it has been proposed to create synergistic composites, because pathogens can find their way to develop resistance against metal nanophases; therefore, it could be important to strengthen and secure their antipathogen potency. These complex materials are comprised of individual components with intrinsic antimicrobial action against a wide range of pathogens. One part consists of inorganic AgNPs, and the other, of active organic molecules with pronounced germicidal effects: both phases complement each other, and the effect might just be the sum of the individual effects, or it can be reinforced by the simultaneous application. Many organic molecules have been proposed as potential candidates and successfully united with inorganic counterparts: polysaccharides, with chitosan being the most used component; phenols and organic acids; and peptides and other agents of animal and synthetic origin. In this review, we overview the available literature and critically discuss the findings, including the mechanisms of action, efficacy and application of the silver-based synergistic antimicrobial composites. Hence, we provide a structured summary of the current state of the research direction and give an opinion on perspectives on the development of hybrid Ag-based nanoantimicrobials (NAMs).

Keywords: antimicrobials; chitosan; hybrid materials; nanocomposites; silver conjugates; silver nanoparticles; synergistic.

Figure 1

(a) Milestones of the antimicrobial medicine and antimicrobial resistance (AMR) development starting from the discovery of penicillin in 1928 and until the present time, where application of antimicrobial composites might work as a missing puzzle in the fight with AMR. (b) Statistics on publications in English (articles and book chapters) using keywords “composites” and “antimicrobial”: total number of documents reached 3906 during years of 2001–2020 and is still growing. Scopus. Available online (https://www.scopus.com, accessed on 23 April 2021).

Figure 2

Examples of development of complex composite systems by various synthetic routes. (a) PEI–Ag⁺/PAA bilayer. Reduction of silver ions within PEI–Ag⁺/PAA films using freshly prepared NaBH₄ yielded an abundance of stable nanoparticles within the multilayered system (LBL). Reprinted with permission Nano Letters 2002, 2, 5, 497–501. Copyright 2002 American Chemical Society [83]. (b) Schematic diagram of CD-MOF template guided synthesis of AgNPs by solution impregnation, followed by reduction, cross-linking and GRGDS surface modification [84]. Copyright 2019 John Wiley and Sons. (c) Schematic illustration of preparation of porous chitosan–silver nanocomposite (PCSSNC) films [87]. Copyright 2010 Elsevier. (d) Schematic representation of the in situ preparation of AgNPs@ HKUST-1@ CFs composites [89]. Copyright 2018 Elsevier.

Figure 2

Examples of development of complex composite systems by various synthetic routes. (a) PEI–Ag⁺/PAA bilayer. Reduction of silver ions within PEI–Ag⁺/PAA films using freshly prepared NaBH₄ yielded an abundance of stable nanoparticles within the multilayered system (LBL). Reprinted with permission Nano Letters 2002, 2, 5, 497–501. Copyright 2002 American Chemical Society [83]. (b) Schematic diagram of CD-MOF template guided synthesis of AgNPs by solution impregnation, followed by reduction, cross-linking and GRGDS surface modification [84]. Copyright 2019 John Wiley and Sons. (c) Schematic illustration of preparation of porous chitosan–silver nanocomposite (PCSSNC) films [87]. Copyright 2010 Elsevier. (d) Schematic representation of the in situ preparation of AgNPs@ HKUST-1@ CFs composites [89]. Copyright 2018 Elsevier.

Figure 3

Overview of the mechanisms of interaction of antimicrobials with the pathogens. (a) Schematic representation of AgNP mechanism of antimicrobial activity [30]. (b) Various antimicrobial mechanisms of chitosan [103]. (c) The schematic representation of the mechanisms of action and their differences of individual bactericides, silver nanoclusters (AgNCs) and antibiotic daptomycin (D) and of the antimicrobial hybrid bomb (D–AgNCs) Reprinted with permission ACS Nano 2016, 10, 7934–7942. Copyright 2016 American Chemical Society [107].

Figure 3

Overview of the mechanisms of interaction of antimicrobials with the pathogens. (a) Schematic representation of AgNP mechanism of antimicrobial activity [30]. (b) Various antimicrobial mechanisms of chitosan [103]. (c) The schematic representation of the mechanisms of action and their differences of individual bactericides, silver nanoclusters (AgNCs) and antibiotic daptomycin (D) and of the antimicrobial hybrid bomb (D–AgNCs) Reprinted with permission ACS Nano 2016, 10, 7934–7942. Copyright 2016 American Chemical Society [107].

Figure 4

Examples of the result of the combination of polysaccharides and derivatives with AgNPs. (a) Comparative effect of CS–AgNPs composite and chitosan, alone (with same 0.024% conc. of CS in both the samples), on recombinant E. coli viability. CS represents chitosan [120]. Copyright 2008 Elsevier. (b) Antibacterial effect of the prepared CSAgHAp coating against E. coli and S. aureus strains [143]. Copyright 2015 Elsevier. (c) Effect of different concentrations of iodinated chitosan–AgNP (at MIC and MBC) and individual components of the composite on the growth of GFP recombinant E. coli. Sample TEM micrographs showing interactions between silver nanoparticles in the iodinated composite and bacteria. Reprinted with permission from Langmuir 2010, 26(8), 5901–5908. Copyright 2010 American Chemical Society [156].

Figure 5

Examples of the result of the combination of phenolic compounds with AgNPs. (a) (I) Schematic diagram illustrating the fabrication and bactericidal process of cAgNPs as a kind of synergistic antibacterial agents; cell death rate of (II) B. subtilis and (III) E. coli bacteria after incubation with cAgNPs, PVP–AgNPs and CCM at different concentrations (12.5, 25, 50, 100, 200 μg/mL) [191]. Copyright 2019 Elsevier. (b) (I) Schematic representation of the obtained AgNPs capped with green tea extract compounds and PEG: (II) HaCat cell viability after incubation with AgNPs and PEG-AgNPs at different concentrations for 24 h [198]. Copyright 2019 Elsevier. (c) (I) Schematics of the process of synthesis of metallic silver (Ag) on the polycaffeic acid (PCA) on etched titanium (Ti) substrate Ti–PCA [200]; (II) graph of inhibition zone for three strains of E. coli, S. aureus and P. aeruginosa for PCA, PCA–Ti and PCA–Ti–Ag [201]. (d) (I) Viral inhibition (%) for virus attachment and penetration experiments with the use of 33 nm and 46 nm AgNPs and 13 nm AgNPs and corresponding carriers; (II) SEM images in EDS mode of HSV-2 virus incubated with AgNPs of different sizes (13, 33, 46 nm).White arrows point out on the interaction spot of the NPs with the surface of virion; white bars indicate 100 nm; (III) kinetics of AgNPs and HSV-2 interaction expressed as % of HSV-2-infected positive controls [203].

Figure 5

Examples of the result of the combination of phenolic compounds with AgNPs. (a) (I) Schematic diagram illustrating the fabrication and bactericidal process of cAgNPs as a kind of synergistic antibacterial agents; cell death rate of (II) B. subtilis and (III) E. coli bacteria after incubation with cAgNPs, PVP–AgNPs and CCM at different concentrations (12.5, 25, 50, 100, 200 μg/mL) [191]. Copyright 2019 Elsevier. (b) (I) Schematic representation of the obtained AgNPs capped with green tea extract compounds and PEG: (II) HaCat cell viability after incubation with AgNPs and PEG-AgNPs at different concentrations for 24 h [198]. Copyright 2019 Elsevier. (c) (I) Schematics of the process of synthesis of metallic silver (Ag) on the polycaffeic acid (PCA) on etched titanium (Ti) substrate Ti–PCA [200]; (II) graph of inhibition zone for three strains of E. coli, S. aureus and P. aeruginosa for PCA, PCA–Ti and PCA–Ti–Ag [201]. (d) (I) Viral inhibition (%) for virus attachment and penetration experiments with the use of 33 nm and 46 nm AgNPs and 13 nm AgNPs and corresponding carriers; (II) SEM images in EDS mode of HSV-2 virus incubated with AgNPs of different sizes (13, 33, 46 nm).White arrows point out on the interaction spot of the NPs with the surface of virion; white bars indicate 100 nm; (III) kinetics of AgNPs and HSV-2 interaction expressed as % of HSV-2-infected positive controls [203].

Figure 6

Examples of the result of the combination of peptides with AgNPs. (a) Schematic representation on GSH–AgNPs composite grafted on glass with TEM and AFM images of E. coli treated with GSH-coated NPs [255]. Reprinted with permission from Langmuir 2012, 28, 8140–8148. Copyright 2012 American Chemical Society. (b) Proposed mechanisms for reduced cytotoxicity and enhanced antimicrobial activity of P-13@AgNPs. Silver ions are reduced to AgNPs in presence of P-13 peptides using NaBH₄ as a reductant. The existing of P-13 between AgNPs and cells isolates the toxic Ag⁺ from cells in the distance (theoretically ~4 nm, with a stretched peptide standing on the surface of AgNPs), which dramatically reduces the cytotoxicity effect on cells. In contrast, the P-13 peptides also endow highly positive charges on the surface of AgNPs, benefiting from the attracting interactions between P-13@AgNPs and negatively charged bacteria [257] Copyright 2020 Elsevier.

Figure 6

Examples of the result of the combination of peptides with AgNPs. (a) Schematic representation on GSH–AgNPs composite grafted on glass with TEM and AFM images of E. coli treated with GSH-coated NPs [255]. Reprinted with permission from Langmuir 2012, 28, 8140–8148. Copyright 2012 American Chemical Society. (b) Proposed mechanisms for reduced cytotoxicity and enhanced antimicrobial activity of P-13@AgNPs. Silver ions are reduced to AgNPs in presence of P-13 peptides using NaBH₄ as a reductant. The existing of P-13 between AgNPs and cells isolates the toxic Ag⁺ from cells in the distance (theoretically ~4 nm, with a stretched peptide standing on the surface of AgNPs), which dramatically reduces the cytotoxicity effect on cells. In contrast, the P-13 peptides also endow highly positive charges on the surface of AgNPs, benefiting from the attracting interactions between P-13@AgNPs and negatively charged bacteria [257] Copyright 2020 Elsevier.