Abstract
Zinc oxide is an essential ingredient of many enzymes, sun screens, and ointments for pain and itch relief. Its microcrystals are very efficient light absorbers in the UVA and UVB region of spectra due to wide bandgap. Impact of zinc oxide on biological functions depends on its morphology, particle size, exposure time, concentration, pH, and biocompatibility. They are more effective against microorganisms such as Bacillus subtilis, Bacillus megaterium, Staphylococcus aureus, Sarcina lutea, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumonia, Pseudomonas vulgaris, Candida albicans, and Aspergillus niger. Mechanism of action has been ascribed to the activation of zinc oxide nanoparticles by light, which penetrate the bacterial cell wall via diffusion. It has been confirmed from SEM and TEM images of the bacterial cells that zinc oxide nanoparticles disintegrate the cell membrane and accumulate in the cytoplasm where they interact with biomolecules causing cell apoptosis leading to cell death.
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Background
Nanotechnology deals with the manufacture and application of materials with size of up to 100 nm. They are widely used in a number of processes that include material science, agriculture, food industry, cosmetic, medical, and diagnostic applications [1,2,3,4,5,6,7,8,9,10]. Nanosize inorganic compounds have shown remarkable antibacterial activity at very low concentration due to their high surface area to volume ratio and unique chemical and physical features [11]. In addition, these particles are also more stable at high temperature and pressure [12]. Some of them are recognized as nontoxic and even contain mineral elements which are vital for human body [13]. It has been reported that the most antibacterial inorganic materials are metallic nanoparticles and metal oxide nanoparticles such as silver, gold, copper, titanium oxide, and zinc oxide [14, 15].
Zinc is an essential trace element for human system without which many enzymes such as carbonic anhydrase, carboxypeptidase, and alcohol dehydrogenase become inactive, while the other two members, cadmium and mercury belonging to the same group of elements having the same electronic configuration, are toxic. It is essential for eukaryotes because it modulates many physiological functions [16, 17]. Bamboo salt, containing zinc, is used as herbal medicine for the treatment of inflammation by regulating caspase-1 activity. Zinc oxide nanoparticles have been shown to reduce mRNA expression of inflammatory cytokines by inhibiting the activation of NF-kB (nuclear factor kappa B cells) [18].
Globally, bacterial infections are recognized as serious health issue. New bacterial mutation, antibiotic resistance, outbreaks of pathogenic strains, etc. are increasing, and thus, development of more efficient antibacterial agents is demand of the time. Zinc oxide is known for its antibacterial properties from the time immemorial [19]. It had been in use during the regime of Pharaohs, and historical records show that zinc oxide was used in many ointments for the treatment of injuries and boils even in 2000 BC [20]. It is still used in sun screen lotion, as a supplement, photoconductive material, LED, transparent transistors, solar cells, memory devices [21, 22], cosmetics [23, 24], and catalysis [25]. Although considerable amount of ZnO is produced every year, very small quantity is used as medicine [26]. The US Food and Drug Administration has recognized (21 CFR 182.8991) zinc oxide as safe [27]. It is characterized by photocatalytic and photooxidizing properties against biochemicals [28].
Zinc oxide has been classified by EU hazard classification as N; R50-53 (ecotoxic). Compounds of zinc are ecotoxic for mammals and plants in traces [29, 30]. Human body contains about 2–3 g of zinc, and the daily requirement is 10–15 mg [29, 31]. No report has demonstrated carcinogenicity, genotoxicity, and reproduction toxicity in humans [29, 32]. However, zinc powder inhaled or ingested may produce a condition called zinc fever, which is followed by chill, fever, cough, etc.
Morphology of zinc oxide nanoparticles depends on the process of synthesis. They may be nanorods, nanoplates [33,34,35], nanospheres [36], nanoboxes [35], hexagonal, tripods [37], tetrapods [38], nanowires, nanotubes, nanorings [39,40,41], nanocages, and nanoflowers [42, 43]. Zinc oxide nanoparticles are more active against gram-positive bacteria relative to other NPs of the same group of elements. Ready to eat food is more prone to infection by Salmonella, Staphylococcus aureus, and E. coli which pose a great challenge to food safety and quality. The antimicrobial compounds are incorporated in the packed food to prevent them from damage. Antimicrobial packaging contains a nontoxic material which inhibits or slows down the growth of microbes present in food or packaging material [44]. An antimicrobial substance for human consumption must possess the following properties.
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a)
It should be nontoxic.
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b)
It should not react with food or container.
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c)
It should be of good taste or tasteless.
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d)
It should not have disagreeable smell.
Zinc oxide nanoparticle is one such inorganic metal oxide which fulfills all the above requirements, and hence, it can safely be used as medicine, preservative in packaging, and an antimicrobial agent [45, 46]. It easily diffuses into the food material, kill the microbes, and prevent human being from falling ill. In accordance with the regulations 1935/2004/EC and 450/2009/EC of the European Union, active packaging is defined as active material in contact with food with ability to change the composition of the food or the atmosphere around it [47]. Therefore, it is commonly used as preservative and incorporated in polymeric packaging material to prevent food material from damage by microbes [48]. Zinc oxide nanoparticles have been used as an antibacterial substance against Salmonella typhi and S. aureus in vitro. Of all the metal oxide nanoparticles studied thus far, zinc oxide nanoparticles exhibited the highest toxicity against microorganisms [49]. It has also been demonstrated from SEM and TEM images that zinc oxide nanoparticles first damage the bacterial cell wall, then penetrate, and finally accumulate in the cell membrane. They interfere with metabolic functions of the microbes causing their death. All the characteristics of the zinc oxide nanoparticles depend on their particle size, shape, concentration, and exposure time to the bacterial cell. Further, biodistribution studies of zinc oxide nanoparticles have also been examined. For instance, Wang et al. [50] have investigated the effect of long-term exposure of zinc oxide nanoparticle on biodistribution and zinc metabolism in mice over 3 to 35 weeks. Their results showed minimum toxicity to mice when they were exposed to 50 and 500 mg/kg zinc oxide nanoparticle in diet. At higher dose of 5000 mg/kg, zinc oxide nanoparticle decreased body weight but increased the weight of the pancreas, brain, and lung. Also, it increased the serum glutamic-pyruvic transaminase activity and mRNA expression of zinc metabolism-related genes such as metallothionein. Biodistribution studies showed the accumulation of sufficient quantity of zinc in the liver, pancreas, kidney, and bones. Absorption and distribution of zinc oxide nanoparticle/zinc oxide microparticles are largely dependent on the particle size. Li et al. [51] have studied biodistribution of zinc oxide nanoparticles fed orally or through intraperitoneal injection to 6 weeks old mice. No obvious adverse effect was detected in zinc oxide nanoparticles orally treated mice in 14 days study. However, intraperitoneal injection of 2.5 g/kg body weight given to mice showed accumulation of zinc in the heart, liver, spleen, lung, kidney, and testes. Nearly ninefold increase in zinc oxide nanoparticle in the liver was observed after 72 h. Zinc oxide nanoparticles have been shown to have better efficiency in liver, spleen, and kidney biodistribution than in orally fed mice. Since zinc oxide nanoparticles are innocuous in low concentrations, they stimulate certain enzymes in man and plants and suppress diseases. Singh et al. [52] have also been recently reviewed the biosynthesis of zinc oxide nanoparticle, their uptake, translocation, and biotransformation in plant system.
In this review, we have attempted to consolidate all the information regarding zinc oxide nanoparticles as antibacterial agent. The mechanism of interaction of zinc oxide nanoparticles against a variety of microbes has also been discussed in detail.
Antimicrobial Activity of Zinc Oxide Nanoparticles
It is universally known that zinc oxide nanoparticles are antibacterial and inhibit the growth of microorganisms by permeating into the cell membrane. The oxidative stress damages lipids, carbohydrates, proteins, and DNA [53]. Lipid peroxidation is obviously the most crucial that leads to alteration in cell membrane which eventually disrupt vital cellular functions [54]. It has been supported by oxidative stress mechanism involving zinc oxide nanoparticle in Escherichia coli [55]. However, for bulk zinc oxide suspension, external generation of H2O2 has been suggested to describe the anti-bacterial properties [56]. Also, the toxicity of nanoparticles, releasing toxic ions, has been considered. Since zinc oxide is amphoteric in nature, it reacts with both acids and alkalis giving Zn2+ ions.
The free Zn2+ ions immediately bind with the biomolecules such as proteins and carbohydrates, and all vital functions of bacteria cease to continue. The toxicity of zinc oxide, zinc nanoparticles, and ZnSO4·7H2O has been tested (Table 1) against Vibrio fischeri. It was found that ZnSO4·7H2O is six times more toxic than zinc oxide nanoparticles and zinc oxide. The nanoparticles are actually dispersed in the solvent, not dissolved, and therefore, they cannot release Zn2+ ions. The bioavailability of Zn2+ ions is not always 100% and may invariably change with physiological pH, redox potential, and the anions associated with it such as Cl− or SO42−.
Solubility of zinc oxide (1.6–5.0 mg/L) in aqueous medium is higher than that of zinc oxide nanoparticles (0.3–3.6 mg/L) in the same medium [101, 102].
Coating of zinc oxide nanoparticles with mercaptopropyl trimethoxysilane or SiO2 reduces their cytotoxicity [103]. On the contrary, Gilbert et al. [104] showed that in BEAS-2B cells, uptake of zinc oxide nanoparticles is the main mechanism of zinc accumulation. Also, they have suggested that zinc oxide nanoparticles dissolve completely generating Zn2+ ions which are bonded to biomolecules of the target cells. However, the toxicity of zinc oxide nanoparticles depends on the uptake and their subsequent interaction with target cells.
Interaction Mechanism of Zinc Oxide Nanoparticles
Nanoparticles may be toxic to some microorganisms, but they may be essential nutrients to some of them [55, 105]. Nanotoxicity is essentially related to the microbial cell membrane damage leading to the entry of nanoparticles into the cytoplasm and their accumulation [55]. The impact of nanoparticles on the growth of bacteria and viruses largely depends on particle size, shape, concentration, agglomeration, colloidal formulation, and pH of the media [106,107,108]. The mechanism of antimicrobial activity of zinc oxide nanoparticles has been depicted in Fig. 2.
Mechanisms of zinc oxide nanoparticle antimicrobial activity
Zinc oxide nanoparticles are generally less toxic than silver nanoparticles in a broad range of concentrations (20 to 100 mg/l) with average particle size of 480 nm [55, 62, 63]. Metal oxide nanoparticles damage the cell membrane and DNA [63, 109,110,111] of microbes via diffusion. However, the production of ROS through photocatalysis causing bacterial cell death cannot be ignored [112]. UV-Vis spectrum of zinc oxide nanoparticle suspension in aqueous medium exhibits peaks between 370 and 385 nm [113]. It has been shown that it produces ROS (hydroxyl radicals, superoxides, and hydrogen peroxide) in the presence of moisture which ostensibly react with bacterial cell material such as protein, lipids, and DNA, eventually causing apoptosis. **e et al. [114] have examined the influence of zinc oxide nanoparticles on Campylobacter jejuni cell morphology using SEM images (Fig. 3). After a 12-h treatment (0.5 mg/ml), C. jejuni was found to be extremely sensitive and cells transformed from spiral shape to coccoid forms. SEM studies showed the ascendency of coccoid forms in the treated cells and display the formation of irregular cell surfaces and cell wall blebs (Fig. 3a). Moreover, these coccoid cells remained intact and possessed sheathed polar flagella. However, SEM image of the untreated cells clearly showed spiral shapes (Fig. 3b). In general, it has been demonstrated from SEM and TEM images of bacterial cells treated with zinc oxide nanoparticles that they get ruptured and, in many cases, the nanoparticles damage the cell wall forcing their entry into it [114, 115].
SEM images of Campylobacter jejuni. a Untreated cells from the same growth conditions were used as a control. b C. jejuni cells in the mid-log phase of growth were treated with 0.5 mg/ml of zinc oxide nanoparticles for 12 h under microaerobic conditions [114]
Zinc oxide nanoparticles have high impact on the cell surface and may be activated when exposed to UV-Vis light to generate ROS (H2O2) which permeate into the cell body while the negatively charged ROS species such as O22− remain on the cell surface and affect their integrity [116, 117]. Anti-bacterial activity of zinc oxide nanoparticles against many other bacteria has also been reported [1, 5, 114, 115]. It has been shown from TEM images that the nanoparticles have high impact on the cell surface (Fig. 4).
a TEM images of untreated normal Salmonella typhimurium cells. b Effects of nanoparticles on the cells (marked with arrows). c, d Micrograph of deteriorated and ruptured S. typhimurium cells treated with zinc oxide nanoparticles [115]
Sinha et al. [118] have also shown the influence of zinc oxide nanoparticles and silver nanoparticles on the growth, membrane structure, and their accumulation in cytoplasm of (a) mesophiles: Enterobacter sp. (gram negative) and B. subtilis (gram positive) and (b) halophiles: halophilic bacterium sp. (gram positive) and Marinobacter sp. (gram negative). Nanotoxicity of zinc oxide nanoparticles against halophilic gram-negative Marinobacter species and gram-positive halophilic bacterial species showed 80% growth inhibition. It was demonstrated that zinc oxide nanoparticles below 5 mM concentration are ineffective against bacteria. The bulk zinc oxide also did not affect the growth rate and viable counts, although they showed substantial decrease in these parameters. Enterobacter species showed dramatic alterations in cell morphology and reduction in size when treated with zinc oxide.
TEM images shown by Akbar and Anal [115] revealed the disrupted cell membrane and accumulation of zinc oxide nanoparticles in the cytoplasm (Fig. 4) which was further confirmed by FTIR, XRD, and SEM. It has been suggested that Zn2+ ions are attached to the biomolecules in the bacterial cell via electrostatic forces. They are actually coordinated with the protein molecules through the lone pair of electrons on the nitrogen atom of protein part. Although there is significant impact of zinc oxide nanoparticles on both the aquatic and terrestrial microorganisms and human system, it is yet to be established whether it is due to nanoparticles alone or is a combined effect of the zinc oxide nanoparticles and Zn2+ ions [55, 106, 109, 119]. Antibacterial influence of metal oxide nanoparticles includes its diffusion into the bacterial cell, followed by release of metal ions and DNA damage leading to cell death [63, 109,110,111]. The generation of ROS through photocatalysis is also a reason of antibacterial activity [62, 112]. Wahab et al. [120] have shown that when zinc oxide nanoparticles are ingested, their surface area is increased followed by increased absorption and interaction with both the pathogens and the enzymes. Zinc oxide nanoparticles can therefore be used in preventing the biological system from infections. It is clear from TEM images (Fig. 5a, b) of E. coli incubated for 18 h with MIC of zinc oxide nanoparticles that they had adhered to the bacterial cell wall. The outer cell membrane was ruptured leading to cell lysis. In some cases, the cell cleavage of the microbes has not been noticed, but the zinc oxide nanoparticles can yet be seen entering the inner cell wall (Fig. 5c, d). As a consequence of it, the intracellular material leaks out leading to cell death, regardless of the thickness of bacterial cell wall.
TEM images of Escherichia coli (a), zinc oxide nanoparticles with E. coli at different stages (b and inset), Klebsiella pneumoniae (c), and zinc oxide nanoparticles with K. pneumoniae (d and inset) [120]
Mechanism of interaction of zinc oxide nanoparticles with bacterial cells has been outlined below [120]. Zinc oxide absorbs UV-Vis light from the sun and splits the elements of water.
Dissolved oxygen molecules are transformed into superoxide, O2−, which in turn reacts with H+ to generate HO2 radical and after collision with electrons produces hydrogen peroxide anion, HO2−. They subsequently react with H+ ions to produce H2O2.
It has been suggested that negatively charged hydroxyl radicals and superoxide ions cannot penetrate into the cell membrane. The free radicals are so reactive that they cannot stay in free and, therefore, they can either form a molecule or react with a counter ion to give another molecule. However, it is true that zinc oxide can absorb sun light and help in cleaving water molecules which may combine in many ways to give oxygen. Mechanism of oxygen production in the presence of zinc oxide nanoparticles still needs experimental evidence.
Zinc oxide at a dose of 5 μg/ml has been found to be highly effective for all the microorganisms which can be taken as minimum inhibitory dose.
Conclusions
Zinc is an indispensable inorganic element universally used in medicine, biology, and industry. Its daily intake in an adult is 8–15 mg/day, of which approximately 5–6 mg/day is lost through urine and sweat. Also, it is an essential constituent of bones, teeth, enzymes, and many functional proteins. Zinc metal is an essential trace element for man, animal, plant, and bacterial growth while zinc oxide nanoparticles are toxic to many fungi, viruses, and bacteria. People with inherent genetic deficiency of soluble zinc-binding protein suffer from acrodermatitis enteropathica, a genetic disease indicated by python like rough and scaly skin. Although conflicting reports have been received about nanoparticles due to their inadvertent use and disposal, some metal oxide nanoparticles are useful to men, animals, and plants. The essential nutrients become harmful when they are taken in excess. Mutagenic potential of zinc oxide has not been thoroughly studied in bacteria even though DNA-damaging potential has been reported. It is true that zinc oxide nanoparticles are activated by absorption of UV light without disturbing the other rays. If zinc oxide nanoparticles produce ROS, they can damage the skin and cannot be used as sun screen. Antibacterial activity may be catalyzed by sunlight, but hopefully, it can prevent the formation of ROS. Zinc oxide nanoparticles and zinc nanoparticles coated with soluble polymeric material may be used for treating wounds, ulcers, and many microbial infections besides being used as drug carrier in cancer therapy. It has great potential as a safe antibacterial drug which may replace antibiotics in future. Application of zinc oxide nanoparticles in different areas of science, medicine, and technology suggests that it is an indispensable substance which is equally important to man and animals. However, longtime exposure with higher concentration may be harmful to living system.
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AH, KSS, AR, and T gathered the research data. AH and KSS analyzed these data and wrote this review paper. All the authors read and approved the final manuscript.
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Siddiqi, K.S., ur Rahman, A., Tajuddin et al. Properties of Zinc Oxide Nanoparticles and Their Activity Against Microbes. Nanoscale Res Lett 13, 141 (2018). https://doi.org/10.1186/s11671-018-2532-3
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DOI: https://doi.org/10.1186/s11671-018-2532-3