Mechanism of Antimicrobial Activity of Green Metallic Nanoparticles

As discussed earlier, metallic NPs are the focus of several biomedical applications, including antimicrobial agents because of their size-and-shape-subordinate tuneable characteristics. Metallic NPs, for example, gold, silver, titanium, copper, zinc, selenium and iron demonstrate strong activity against MDR bacteria (Marslin et al., 2018; Alavi and Karimi, 2018; Srihasam et ah, 2020). Significantly, green-synthesized NPs are suitable for different antimicrobial applications due to their strong stability and biocompatibility. NPs’ mechanisms of action responsible for their antimicrobial effect flow from the release of metal ions, oxidative stress as well as non-oxidative stress that happens simultaneously (Zaidi et ah, 2017). These green NPs can target the bacterial cells and disrupt critical functions of the cell membranes, causing severe impacts on the respiration and permeability of membranes. In addition, G-NPs interact with intracellular components (proteins and nucleic acids), which inhibit many biological processes such as gene transfer and cell division (Dakal et ah, 2016; Slavin et ah, 2017). The mechanism of action of G-NPs and antibiotics appear to be similar in terms of interfering with the synthesis of protein, RNA, DNA and membrane disruption (Kohanski et ah. 2010; Dakal et ah, 2016). However, these metallic NPs and G-NPs antimicrobial activities hail from multiple mechanisms, invaluable in terms of limiting the ability bacteria developing resistance to them (Slavin et ah, 2017). To develop resistance against these nanoparticles, the bacterial cells must obtain multiple gene mutations concurrently, which is highly unlikely. In addition, synthesizing metallic NPs using green methods allow bioactive compounds, proteins and polysaccharides to bind with nanoparticles. This enhances NPs antimicrobial activity against MDR bacteria. Figure 10.6 summarizes the possible mechanisms of action of G-NPs against bacteria.

Potential Medicinal Plants for Green Synthesis of NPs against Multidrug Resistance S. aureus

Staphylococcus aureus strains are pathogenic bacteria that have developed resistance to multiple drugs and so cause severe infections, in both hospitals and the wider community. Worse is that this bacterium can continually adapt, becoming even more resistant over time. Thus, attention has turned to finding novel treatment solutions to overcome this bacterium and its associated diseases, specifically using medicinal plants. Many reports have explored medicinal plants and/or their phytochemicals to cure 5. aureus and its associated diseases. The antimicrobial potential of medicinal plants and phytochemicals against S. aureus (MRSA, VISA, VRSA and MSSA) have been addressed in several scientific studies. Previously tested plants showed antibacterial activity against both gram-positive and gram-negative bacteria, including MDR S. aureus.

In this regard, Talib and Mahasneh (20Ю) reported that the MIC value of Rosa damascene receptacles butanol and aqueous extracts were found to be 500 pg/ml, while MIC for Inula viscosa flowers butanol extract was 250 pg/ml. MRSA was found to be inhibited using butanol, Rosa damascena receptacles aqueous extracts as well as Inula viscosa flowers butanol extract (MIC values equals 500, 500 and 250 pg/ml), respectively. Meanwhile, MRSA was sensitive to Rosa damascena receptacles’ ethanol extract with 95% inhibition, Verbascum sinaiticum flowers ethanol extract with 70% inhibition and Inula viscosa flowers ethanol extract with 92% inhibition. These results were attributed to phytochemicals present in plant extracts such as terpenoids and flavonoids, as well as alkaloids found in Narcissus tazetta aerial parts and Ononis hirta aerial parts. Great attention has been paid to the phytochemicals of plants, especially those linked to antimicrobial activity such as flavonoids, triterpenes, alkaloids, sesquiterpene lactones, diterpenes and naphthoquinones. Phytochemicals were isolated and tested for their antimicrobial activities (Rios and Recio, 2005). For instance, flavonoids are commonly found in plant parts such as seeds, fruits, flowers, vegetables and stems. Many investigations have been undertaken to determine the flavonoids antibacterial mechanisms. In this regard, quercetin activity was found to be partly responsible for DNA gyrase inhibition. Epigallocatechin gallate and sophoraflavone hampered the metabolic functions of the cell membrane functions (Cushnie and Lamb, 2005). Meanwhile, flavonostil- benes exhibited unique antibacterial and antibiofilm effects against S. epidermidis with MIC of 3.1-12.5 pg/ml (Wan et al., 2015).

Rad et al. (2013) reported that Xanthium strumarium extract (at the 300 pi concentration) had the highest effect against MSSA (25 mm) and MRSA (20 mm) strains. Moreover, there was a correlation between the plant extract’s concentration and bacterial growth inhibition. The antibacterial activity of X. strumarium extract could possibly be attributed to the flavonoids, phenolic acids, terpenoids and tannins present. The ethanolic extract of Saussurea lappa root was tested against MDR bacteria, including MRSA (Hasson et al., 2013). For MRSA, the bacteriostatic effect occurred at 2,000 pg/ml concentration, while the bactericidal effect occurred at 6,000 pg/ml concentration. Manubolu et al. (2013) investigated and identified the antibacterial S. aureus components from ethyl acetate, chloroform, methanol hexane and aqueous extracts of Senecio tenuifolius Burm. F. (S. tenuifolius) and their antibacterial effect was tested against 5. aureus (ATCC 25923), MRSA and MSSA. Methanol extracts were found to significantly decrease the growth of 5. aureus (ATCC 25923), MRSA and MSSA with the maximum inhibition zone at 16.23, 14.06 and 15.23 mm and MIC of 426.16, 683.22 and 512.12 pg/ml, respectively. To investigate the active component, the methanol extract was purified using column chromatography. Four fractions (Stl, St2, St3 and St4) were obtained. St3 fraction was the most effective fraction against S. aureus (ATCC 25923), MRSA and MSSA, with the maximum inhibition zone at 15.09, 13.25 and 14.12 mm and the maximum MIC of 88.16, 128.11 and 116.12 pg/ ml, respectively. GC-MS analysis revealed that St3 fraction contains hydroquinone, 3-[methyl-6,7-dihydro benzofuran-4(5#)-one], 1,2-benzenedicarboxylic acid, methyl ester as well as three unknown compounds. The study concluded that medicinal plants (S. tenuifolius) have the potential to treat skin infections and combat MRSA and its associated diseases (Manubolu et ah, 2013). Similarly, compounds with antibacterial activity were isolated from the roots of Atractylodes japonica (A. japonica) and further characterized. Four compounds were isolated and identified as (1): atractylenolide III, (2): atractylenolide I, (3): diacetylatractylodiol [(6E,12E)-tetradeca-6,12-diene-8,10 -diyne-l,3-diol diacetate, TDEYA, and (4): (6E,12E)-tetradecadiene-8,10-diynel,3-di ol (TDEA). The compound number (4) showed antibacterial activity against all tested MRSA isolates with MIC values from 4 to 32 pg/ml. Similar findings were noted with other solvents fractions. However, the chloroform fraction exhibited the highest antibacterial activity against MRSA, which could be attributed to its bioactive components (Jeong et ah, 2010). Results reveal the antibacterial effect of medicinal plants (A. japonica) and their extracts against MRSA.

In the search for alternative solutions against MRSA, the stem bark and leaf of Tabernaemontana alternifolia (Roxb) (an indigenous Indian medicine used to treat skin infections) were tested to determine their antibacterial activity against MRSA. T. alternifolia stem bark aqueous extracts showed antibacterial effects against MRSA and VRSA. The MIC values ranged from 600 to 800 pg/ml for MRSA. The phytochemical profiling showed that saponins, alkaloids, coumarins, flavonoids and steroids were present. Moreover, T. alternifolia extract did not show any cytotoxic activity towards Vero cells, making the extract a good candidate to treat MRSA infections (Marathe et ah, 2013). This is also true for Tabernaemontana stapfiana (Britten) where different solvents of root and stem extracts showed good antibacterial activity. The phytochemical profiling showed that tannins, alkaloids, coumarins, flavonoids and saponins were present, all of which are associated with antimicrobial effects. The methanolic extract exhibited good antibacterial effects against the tested bacterial strains, including MRSA with MIC ranging between 15.6 and 500 mg/ml. MBC ranged between 31.25 and 500 mg/ml (Ruttoh et ah, 2009).

The antibacterial effect of several solvents, as well as aqueous extracts of oregano, neem, bryophyllum, tulsi, aloe vera, rosemary, lemongrass and thyme were evaluated on 10 MDR clinical isolates (Dahiya and Purkayastha, 2012). Methanol and ethanol extracts showed significant inhibitory effects against most tested bacteria. S. aureus were the most inhibited bacteria in 24 of the extracts (60%). The MIC values of tulsi, rosemary, oregano, and aloe vera extracts were found to be in the range of 1.56-6.25 mg/ml when tested against MRSA. Phytochemical profiling showed the presence of saponins and tannins in all tested plants. Bioautography agar overlay analysis and TLC of ethanol extracts of tulsi, neem and aloe vera demonstrated that tannins and flavonoids are the main active compounds against MRSA (Dahiya and Purkayastha, 2012). Ursolic and oleanolic acids both were isolated from the leaves of Salvia officinalis (Sage) and these acids exhibited antibacterial effects against VRE, MRSA and Streptococcus pneumoniae. The antimicrobial effect of ursolic acid on VRE, MRSA and S. pneumoniae were double that of oleanolic acid (determined by calculating values from MIC) (Horiuchi et al., 2007).

Premna resinosa (Hochst.) Schauer is a medicinal plant used in the treatment of respiratory illnesses. P. resinosa has strong antibacterial effects against tuberculous with MIC value of <6.25 pg/ml in the fraction of ethyl acetate. Dichloromethane fraction, however, exhibited the maximum antibacterial MIC of 31.25 pg/ml towards MRSA. Meanwhile, ethyl acetate fraction showed the best inhibition zone of 22.3 ± 0.3 towards S. aureus. The antibacterial activity was associated with the detected anthraquinones, alkaloids, terpenoids, flavonoids and phenols in plant extracts. The study showed that P. resinosa is a high-potential source for novel antibacterial, antituberculous and antifungal drugs, with a possible strong effect against MRSA, C. albicans, S. aureus and Mycobacterium tuberculosis (MTB), which are well known as public health challenge (Njeru et al., 2015).

Hydrastis canadensis L. (golden seal) is a medicinal plant traditionally used in skin infections treatment. Cech et al. (2012) reported the activity of H. canadensis leaf extracts against MRSA. H. canadensis extract exhibited a higher antimicrobial effect than the alkaloid berberine alone as MICs values were found to be 75 and 150pg/ml, respectively. LC-MS analysis detected alkaloids and flavonoids (efflux- pump inhibitory phytochemical) in the extract, which may explain the improved efficacy of H. canadensis in comparison to the berberine alone. The extract of H. canadensis has an anti-quorum sensing effect on MRSA, which can be attributed to the cell signalling reduction of the AgrCA two-component regulatory system (TCS). This extract was also found to inhibit the MRSA toxin production and damage keratinocytes. The antimicrobial activity of Rumex nervosus (aerial part) was evaluated against S. aureus, MRSA, E.faecalis, E. coli, P. aeruginosa and Candida albicans. The results showed that medicinal plants’ polar extracts have significant antimicrobial effects. Among gram-positive bacteria, R. nervosus extract showed a dose-dependent growth inhibition effect against 5. aureus and MRSA (Al-Asmari et al., 2015). In contrast, the antibacterial effect of non-polar extracts exhibited higher antimicrobial effect against MRSA compared to polar extracts (Ahmad et al., 2014). Lemongrass chloroform and hexane extracts were ineffective on the studied bacteria (MRSA, S. aureus, K. pneumoniae, E. coli and P. mirabilis). The reason for this minimal antibacterial effect could be attributed to the low concentration of phytochemicals in these extracts (Dahiya and Purkayastha, 2012). The medicinal plant of Eleucine indica is traditionally used to treat diseases of the kidneys and liver. Its therapeutic effect is often linked to their antioxidant characteristics. Hexane extract in particular showed a remarkable antibacterial effect against MRSA (Al-Zubairi et al., 2011). Similarly, Aliahmadi et al. (2014) reported that the highest antibacterial activities were found in the hexane extract of Bromus inermis Leyss Inflorescences. Hexane extract had a significant impact on MRSA with 8 pg/ml MIC value.

Rhodomyrtus tomentosa leaf ethanolic extract showed significant antibacterial effect against both MRSA and 5. aureus ATCC 29213. Its MIC values range between 31.25 and 62.5 pg/ml, and the MBC was 250 pg/ml. The impact of rhodo- myrtone on the expression of MRSA’s cellular protein has been studied using pro- teomic approaches in order to provide insights into the antibacterial mechanisms involved. Proteome analyses show that the subinhibitory concentration of rhodo- myrtone (0.174 pg/ml) influences the expression of multiple main functional classes of MRSA whole cell proteins. Transmission electron micrographs revealed rhodo- myrtone impacts in the treated MRSA, notably ultrastructural and morphological alterations. Important biological processes in cell division and cell wall biosynthesis were found to be interrupted. Significant changes included cellular disintegration, cell wall alterations, formation of abnormal septum and cell lysis. Abnormal shape and size of Staphylococcal cells were observed in the treated MRSA cells (Sianglum et al., 2011).

The ability of MRSA to form biofilms is one of the major attributes in its pathogenicity. In this regard, de Araujo et al. (2015) evaluated the antibiofilm, antibacterial and cytotoxic impacts of Terminalia fagifolia stem bark ethanol extract (EtE) as well as the three extract fractions (HaF, AqF and WSF). It was noticed that antibacterial effect MICs values of EtE and the fractions were in the range of 25-200 pg/ml; meanwhile, the MBCs values ranged from 200 to 400 pg/ml. The antibiofilm activity of both the EtE and the FlaF, AqF and WSF fractions exhibited remarkable biofilm formation inhibition, in over 80% of the tested strains. Microscopic images from the AFM show changes in morphology in addition to significant size alterations of S. aureus ATCC 29213 surface, caused by AqF.

Quercus infectoria G. Olivier nutgall is well known in traditional Thai medicine as an efficient drug for skin and wound infections. Chusri and Voravuthikunchai (2011) reported the effect of different Q. infectoria fractions and its purified compounds against MRSA and S. aureus, which caused hypersensitivity to low and high osmotic pressure. The synergistic effect of Q. infectoria extract with (3-lactam antibiotics have shown that Q. infectoria can interfere with the Staphylococcal enzymes, including |3-lactamase and autolysins (Chusri and Voravuthikunchai, 2009). Results also show that Q. infectoria extract as well as tannic acid influences the biofilm formation, bacterial cell surface hydrophobicity and the cell wall, which might impact on the anti-formation activity of biofilm (Chusri et al., 2012).

In addition to the above-mentioned studies, many reports evaluated the antimicrobial potential of medicinal plants as well as its purified phytochemicals against MRSA such as Rosa canina L. (rose red), Cinnamomum iners, Camellia sinensis, Juglans regia, Psoralea corylifolia, Abrus schimperi, Atuna racemose, Tectona grandis, and Plectranthus amboinicus (Lour.) among others (Shiota et al., 2000; Neamatallah et al., 2005; Buenz et al.. 2007; Mustaffa et al., 2011; Rahman et al., 2011; de Oliveira et al., 2013; Farooqui et al., 2015; Cui et al,. 2015).

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