Materials Science and Engineering C 44 (2014) 278–284
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Materials Science and Engineering C journal homepage: www.elsevier.com/locate/msec
Review
Antimicrobial activity of the metals and metal oxide nanoparticles Solmaz Maleki Dizaj a, Farzaneh Lotfipour a, Mohammad Barzegar-Jalali a, Mohammad Hossein Zarrintan a, Khosro Adibkia b,⁎ a b
Drug Applied Research Center and Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran Biotechnology Research Center and Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
a r t i c l e
i n f o
a b s t r a c t
Article history: Received 7 May 2014 Received in revised form 5 July 2014 Accepted 8 August 2014 Available online 16 August 2014
The ever increasing resistance of pathogens towards antibiotics has caused serious health problems in the recent years. It has been shown that by combining modern technologies such as nanotechnology and material science with intrinsic antimicrobial activity of the metals, novel applications for these substances could be identified. According to the reports, metal and metal oxide nanoparticles represent a group of materials which were investigated in respect to their antimicrobial effects. In the present review, we focused on the recent research works concerning antimicrobial activity of metal and metal oxide nanoparticles together with their mechanism of action. Reviewed literature indicated that the particle size was the essential parameter which determined the antimicrobial effectiveness of the metal nanoparticles. Combination therapy with the metal nanoparticles might be one of the possible strategies to overcome the current bacterial resistance to the antibacterial agents. However, further studies should be performed to minimize the toxicity of metal and metal oxide nanoparticles to apply as proper alternatives for antibiotics and disinfectants especially in biomedical applications. © 2014 Elsevier B.V. All rights reserved.
Keywords: Antimicrobial activity Metal nanoparticles Metal oxide nanoparticles Reactive oxygen species
Contents 1. Introduction . . . . . . . 2. Ag and Ag2O nanoparticles 3. ZnO nanoparticles . . . . 4. TiO2 nanoparticles . . . . 5. Au nanoparticles . . . . . 6. Si and SiO2 nanoparticles . 7. MgO and CaO nanoparticles 8. Cu and CuO nanoparticles . 9. Conclusion . . . . . . . . References . . . . . . . . . .
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1. Introduction Emergence of the antibiotic resistance pathogens has become a serious health issue and thus, numerous studies have been reported to improve the current antimicrobial therapies. It is known that over 70% of bacterial infections are resistant to one or more of the antibiotics that are generally used to eradicate the infection [1]. Development of ⁎ Corresponding author at: Faculty of Pharmacy, Tabriz University of Medical Sciences, Golgasht Street, Daneshgah Ave., Tabriz, Iran. Tel.: +98 411 3341315; fax: + 98 411 3344798. E-mail address: [email protected] (K. Adibkia).
http://dx.doi.org/10.1016/j.msec.2014.08.031 0928-4931/© 2014 Elsevier B.V. All rights reserved.
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new and effective antimicrobial agents seems to be of paramount importance. The antimicrobial activity of metals such as silver (Ag), copper (Cu), gold (Au), titanium (Ti), and zinc (Zn), each having various properties, potencies and spectra of activity, has been known and applied for centuries [2]. Recently, nanotechnology has offered great possibilities in various fields of science and technology. Pharmaceutical nanotechnology with numerous advantages has growingly attracted the attention of many researchers [3]. The application of nanomaterials in the drug delivery systems has been investigated for more than twenty years bringing about innovation of dosage forms with improved therapeutic effects and physicochemical characteristics [4,5]. Several types of nanoparticles
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and their derivatives have received great attention for their potential antimicrobial effects. Metal nanoparticles such as Ag, silver oxide (Ag2O), titanium dioxide (TiO2), silicon (Si), copper oxide (CuO), zinc oxide (ZnO), Au, calcium oxide (CaO) and magnesium oxide (MgO) were identified to exhibit antimicrobial activity. In vitro studies revealed that metal nanoparticles inhibited several microbial species. The kind of the materials used for preparing the nanoparticles as well as the particle size were two important parameters that affected the resultant antimicrobial effectiveness [6,7]. Generally nanoparticles have different properties compared to the same material with the larger particles owing to the fact that the surface/volume ratio of the nanoparticles increases considerably with decrease in the particle size [8,9]. Indeed, in the nanometer dimensions, fraction of the surface molecule is noticeably increased which in turn improves some properties of the particles e.g. heat treatment, mass transfer, dissolution rate, catalytic activity [8,10]. The exact mechanisms for antibacterial effect of nanometals are still being investigated, but there are two more popular proposed possibilities in this regard: (a), free metal ion toxicity arising from dissolution of the metals from surface of the nanoparticles and (b), oxidative stress via the generation of reactive oxygen species (ROS) on surfaces of the nanoparticles [11]. Furthermore, morphological and physicochemical characteristics of the nanometals have been proven to exert an effect on their antimicrobial activities [6,12]. It is known that the small nanoparticles have the strongest bactericidal effect [8,11,13,14]. The positive surface charge of the metal nanoparticles facilitates their binding to the negatively charged surface of the bacteria which may result in an enhancement of the bactericidal effect [6]. The shape of the nanoparticles also influences their antimicrobial effects [15,16]. In this article, we focused on the latest findings about antimicrobial activity of the most commonly employed nanometals and their mechanism of action. Owing to the promising development and the vast application of nanoparticles, understanding the nanotoxicity and its outcomes is necessary. For years, pharmaceutical sciences have used nanoparticles to reduce toxicity and side effects of the drugs; nevertheless, there are some safety concerns about the nanoparticles. According to the reports, neurological and respiratory damage, circulatory problems and some other toxicity effect of nanoparticles are the main concerns in use of the nanoparticles [17–19]. Indeed, several types of the nanoparticles appear to be non-toxic and some of them are rendered non-toxic with beneficial health effects [20]. Appling antimicrobial activity of the nanoparticles to eradicate bacterial infections could be considered as one of these valuable health issues. 2. Ag and Ag2O nanoparticles According to literature Ag nanoparticles are the most popular inorganic nanoparticles used as antimicrobial agents [21]. The antimicrobial application of Ag additives is widely benefitted in the various injectionmolded plastic products, textiles and coating-based usages [22]. Ag nanoparticles also possess a range of biomedical applications [2]. It has been revealed that, Ag nanoparticles show a high antimicrobial activity comparable with its ionic form [23]. It has also been demonstrated that Ag nanoparticles are potential antimicrobial agents against drugresistant bacteria [1]. According to literature, antibacterial action of Ag nanoparticles results from damage of the bacterial outer membrane [24]. Some researchers suppose that, Ag nanoparticles can induce pits and gaps in the bacterial membrane and then fragment the cell [25, 26]. It has also been known that Ag ions interact with disulfide or sulfhydryl groups of enzymes that lead to disruption of metabolic processes which in turn cause the cell death [22]. Jo et al. investigated the effect of size reduction on the antimicrobial effect of Ag nanoparticles. They used Ag nanoparticles to control Bipolaris-sor Okiniana and Magnaporthe Grisea. Similarly, they also evaluated the efficacy of Ag nanoparticles on different types of pathogens
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such as soilborne fungi which rarely produce spores. According to their results, Ag nanoparticles (20 to 30 nm) could better penetrate and colonize within the plant tissue. They suggested that, Ag nanoparticles had a great potential for use in controlling spore-producing fungal plant pathogens. They suggested that these nanoparticles might be less toxic than synthetic fungicides [23]. In the other study, Mie and et al. tested the antibacterial activity of their synthesized Ag nanoparticles (19 nm) against eight micro-organisms using the disk diffusion method. Their results revealed that the Ag nanoparticles showed potential antibacterial activity against Gram-negative bacteria. Thus, the authors suggested that these synthesized Ag nanoparticles could be applied in the pharmaceutical and biomedical industries [27]. Hernández-Sierra et al. reported comparative investigation of the bactericidal activity of Ag nanoparticles, ZnO, and Au on Streptococcus mutans (S. mutans). Their results indicated that Ag nanoparticles exhibited the most activity for controlling S. mutans. The authors suggested that Ag nanoparticles could be used in dental caries since it commonly is caused by S. mutans [28]. Likewise, Besinis et al. investigated the antibacterial effect of Ag nanoparticles on S. mutans. Their results showed that the antibacterial effect of Ag nanoparticles against S. mutans was more superior than that of chlorhexidine [11]. Zarei et al. evaluated antibacterial effect of Ag nanoparticles against four foodborne pathogens namely Listeria monocytogenes, Escherichia coli (E. coli), Salmonella typhimurium (S. typhimurium) and Vibrio parahaemolyticus. According to their results, Ag nanoparticles had great antibacterial effect on the mentioned pathogens. They concluded that Ag nanoparticles could be a good alternative for cleaning and disinfection of equipment and surfaces in the food-related environments [29]. Beside the particle size reduction, shape-dependent properties of nanoparticles have also been investigated by researchers. Pal et al. reported the shape dependent antibacterial activity of Ag nanoparticles (in three different forms: spherical, rod-shaped and truncated triangular). According to their findings, truncated triangular nanoparticles were more reactive due to their high-atom-density surfaces, and therefore showed higher antimicrobial activity [15]. In the other study, Bera et al. stated the size and shape-dependent antimicrobial activity of fluorescent Ag nanoparticles (1–5 nm) against Gram-positive (Staphylococcus epidermidis and Bacillus megaterium) and Gram-negative bacteria (Pseudomonas aeruginosa). They emphasized that the shape and size of the particles controlled their activity. According to these investigations, the smaller particles easily penetrated the cell wall and showed the enhanced antimicrobial activity. The authors suggested that these Ag nanoparticles could be used for different purposes such as clinical wound dressing, bioadhesives, biofilms and the coating of biomedical materials [16]. Bahrami prepared Ag–Au alloy nanoparticles to evaluate their antimicrobial effect against Staphylococcus aureus (S. aureus). The antibacterial activity of Ag–Au alloy nanoparticles was intensified when they combined with penicillin G and piperacillin. The authors suggested that Ag–Au alloy nanoparticles could be used as an adjuvant in combination therapy of antibiotics [30]. Ag2O nanoparticles have also been discovered to have great antimicrobial activity [1]. It is believed that, metal oxide nanoparticles might be considered as a novel alternative to the most antibiotics [1,31]. Sondi and Salopek-Sondi demonstrated antimicrobial efficacy of Ag2O nanoparticles against E. coli. They proposed that when E. coli were exposed to these nanoparticles, DNA lost its replication ability and the cell cycle halted at the G2/M phase owing to the DNA damage. Then the cells were affected by oxidative stress, and apoptosis was induced [32]. Furthermore, Ag had reported to be less toxic than many other disinfectants. Marambio-Jones and Hoek had reviewed the antibacterial mechanisms of the Ag nanoparticles and potential implications for human health and environment [33]. We think that further research should be performed to develop Ag compounds, composites and alloys with the minimum toxicity and maximum antimicrobial effect.
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3. ZnO nanoparticles
4. TiO2 nanoparticles
Safety of ZnO and its compatibility with human skin make it a suitable additive for textiles and surfaces that come in contact with the human body [34,35]. ZnO nanoparticles showed bactericidal effects on Gram-positive and Gram-negative bacteria as well as the spores which are resistant to high temperature and high pressure [36]. The improved antibacterial activity of ZnO nanoparticles compared to its microparticles was related to the surface area enhancement in the nanoparticles [6,37,38]. Padmavathy et al. investigated the antibacterial activity of ZnO nanoparticles with various particle sizes. Their results demonstrated that the bactericidal efficacy of ZnO nanoparticles increased by decreasing particle size [38]. Azam et al. reported comparative investigation of antimicrobial activity of ZnO, CuO, and Fe2 O 3 nanoparticles against Gramnegative (E. coli and P. aeruginosa) and Gram-positive (S. aureus and Bacillus subtilis (B. subtilis)) bacteria. According to their results, the most bactericidal activity was reported for the ZnO nanoparticles while Fe2 O3 nanoparticles exhibited the least antibacterial effect [36]. In particular, ZnO reduces the bacteria viability; however, the exact mechanism of its antibacterial activity has not been well understood so far. One proposed possibility is the generation of hydrogen peroxide as a main factor of the antibacterial activity. It is also believed that, the accumulation of the particles on the bacteria surface due to the electrostatic forces could be another mechanism of the antibacterial effect of ZnO particles [39]. Besides, ROS generated on the surface of the particles, zinc ion release, membrane dysfunction, and nanoparticles internalization could also be taken into account as the possible reasons of the cell damage [40]. Moreover, interruption of transmembrane electron transportation has been stated in the case of some metal nanoparticles such as Ag and Zn [41–43]. Xie et al. evaluated antibacterial activity of ZnO nanoparticles against Campylobacter jejuni (C. jejuni). They suggested that the antibacterial mechanism of ZnO nanoparticles might be due to disruption of the cell membrane and oxidative stress in C. jejuni. Their results signified that ZnO nanoparticles caused morphological changes, measurable membrane leakage, and increase (up to 52-fold) in oxidative stress gene expression in C. jejuni [37]. Ag nanoparticles showed antibacterial activity even in the ultra-low concentrations [44]; however, the antibacterial activity of ZnO nanoparticles depended on the concentration and surface area. Thus ZnO nanoparticles in higher concentrations and larger surface area displayed better antibacterial activity [8]. Hossein-khani et al. investigated the antibacterial characteristics of ZnO nanoparticle against Shigella dysenteriae. Based on their results, a considerable decrease in the bacteria number was observed as a result of particles size reduction [45]. Emami-Karvani et al. investigated the antimicrobial activity of ZnO nanoparticles against Gram-negative (E. coli) and Gram-positive (S. aureus) bacteria. They evaluated the effects of concentration and particle size reduction on the antibacterial activity of ZnO nanoparticles. They found that the antibacterial activity of ZnO nanoparticles increased with decreasing particle size and enhancing powder concentration; nonetheless, ZnO bulk powder showed no significant antibacterial activity [46]. Some studies have shown that preparation of metal ion doped nanoparticles can improve antimicrobial properties of metal nanoparticles [47–49]. Sun et al. synthesized the titanium-doped ZnO powders from different zinc salts. Their results showed that the titanium doped ZnO powders had the antibacterial action against E. coli and S. aureus. The authors emphasized that the antibacterial properties of the titaniumdoped ZnO powders were related to the particle size reduction and the crystallinity [48]. Moreover, ZnO nanoparticles exhibit high photocatalytic properties which improve their antimicrobial efficiency [44]. ZnO nanoparticles produce ROS under UV light as well [50].
Antimicrobial property of TiO2 is related to its crystal structure, shape and size [51]. It is proposed that oxidative stress via the generation of ROS may be a particularly important mechanism for TiO2 nanoparticles (anatase forms). Then ROS cause site specific DNA damage [44,52]. Roy et al. evaluated the effect of TiO2 nanoparticles with different antibiotics against methicillin-resistant S. aureus (MRSA). They reprted that, TiO2 nanoparticles improved the antimicrobial effect of beta lactums, cephalosporins, aminoglycosides, glycopeptides, macrolids, lincosamides and tetracycline against MRSA. In another experiment, their results showed that antimicrobial resistance of MRSA against various antibiotics decreased in the presence of TiO2 nanoparticles [52]. Haghighi et al. investigated antifungal effect of TiO2 nanoparticles on the fungal biofilms (fluconazole resistant standard strains of Candida albicans (C. albicans)). According to their results, the synthesized TiO2 nanoparticles had improved antifungal effect on the fluconazole resistant strain of C. albicans biofilms. The authors suggested that TiO2 nanoparticles could effectively inhibit the fungal biofilms especially those formed on the surface of medical devices [51]. Photocatalytic properties of the TiO2 nanoparticles help them to efficiently eradicate the bacteria. In fact, TiO2 nanoparticles produce ROS under UV light. Carré et al. considered that the antibacterial photocatalytic activity was accompanied by lipid peroxidation that causes to enhance membrane fluidity and disrupt the cell integrity [53]. However, the use of TiO2 nanoparticles under UV light is restricted because of genetic damage in human cells and tissues [1]. It has been proved that, doping of TiO2 nanoparticles with metal ions can be a good idea to overcome this problem. In addition, antibacterial and photocatalytic properties of TiO2 nanoparticles are significantly enhanced by doping them with metal ions [1,47]. In other words, doping with metal ions shifts TiO2 nanoparticles' light absorption range to visible light and therefore, there is no need to irradiate them with UV light [1]. Conjugation of TiO2 nanoparticles with nontoxic polymers is another approach to overcome toxicity problems of TiO2 nanoparticles. For instance, Rafailovich et al. reported that TiO2 nanoparticles–polymer conjugates were harmless to fibroblast cells [1]. 5. Au nanoparticles Au nanoparticles are considered to be so valuable in the development of antibacterial agents due to their nontoxicity, high ability to functionalization, polyvalent effects, ease of detection and photothermal activity [54–57]. Although generation of ROS is the main cause of cellular death for most antibiotics and antibacterial nanomaterials; nevertheless, antimicrobial activity of Au nanoparticles do not induce any ROS-related process [58]. Cui et al. proved that antibacterial activity of the Au nanoparticles was attributable to 1) attachment of these nanoparticles to the bacterial membrane followed by membrane potential modification and ATP level decrease and 2) inhibition of tRNA binding to the ribosome [58]. Tiwari et al. investigated the antibacterial and antifungal activities of the Au nanoparticles functionalized with 5-fluorouracil against Micrococcus luteus, S. aureus, P. aeruginosa, E. coli, Aspergillus fumigates (A. fumigates), and Aspergillus niger (A. niger). The authors reported that these nanoparticles showed more activity on Gram negative bacteria than Gram positive ones due to their easier internalization into the Gram negative bacteria. These nanoparticles indicated antifungal activity against A. fumigates and A. niger as well [55]. Zhou et al. tested antibacterial activities of Au and Ag nanoparticles against E. coli and bacillus Calmette-Guérin (BCG). They claimed that, Au and Ag nanoparticles exhibited significant antibacterial activity against both Gram negative (E. coli) and the Gram positive bacteria (BCG). They also functionalized Au nanoparticles with a strongly bound capping (poly-allylamine hydrochloride) and a weakly bound
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capping agent (citrate). Poly-allylamine hydrochloride could directly contact with the bacterial cell membrane due to its positively charged nature [59]. Furthermore, Au nanoparticles functionalized with strongly bound capping agents could self-assemble into 4–5 μm long chains [60]. Zhou et al. explained that these two mentioned processes facilitate the delivery of a large number of Au nanoparticles on the bacterial cell wall. Conversely, extra-aggregation of weakly bound capping agents like citrate causes reduced surface area and so decreased interactions with the nanoparticles. Accordingly, Au nanoparticle with the same shape and size but different capping agent exhibits different antimicrobial activities [56]. In another study, Lima et al. reported antimicrobial effect of Au nanoparticles (5 nm) against E. coli and Salmonella typhi (S. typhi) bacteria. Their results showed that, these nanoparticles reduced 90–95% of E. coli and S. typhi colonies. The authors emphasized that, the main factors that influenced the biocidal properties were the roughness and the dispersion of the Au nanoparticles on the medium [54]. It seems that Au nanoparticles are safer to the mammalian cells than the other nanometals due to the ROS-independent mechanism of their antimicrobial activity. Moreover, high ability of these nanoparticles for functionalization makes them ideal nanomaterials to be applied as targeted antimicrobial agents. 6. Si and SiO2 nanoparticles Antimicrobial activity of SiO2 would become more significant at nano-scale owing to the increased surface area [61]. Cousins et al. found that Si nanoparticles inhibited bacterial adherence to oral biofilms [62]. Combination use of Si nanoparticles with the other biocidal metals such as Ag has been extensively studied in the recent years. Egger et al. reported the production and investigation of antimicrobial activity of novel Ag–Si nanocomposite. Their results revealed better antimicrobial effect of the nanocomposite against a wide range of microorganisms compared to conventional materials, such as silver nitrate and silver zeolite [22]. In the other study, Mukha et al. synthesized Ag/SiO2 and Au/SiO2 nanostructures and investigated their antimicrobial activity. The results showed that Ag/SiO2 nanocomposites indicated improved antimicrobial properties against E. coli, S. aureus, and C. albicans while Au/SiO2 nanocomposites did not show any antibacterial activity against the mentioned microorganisms. The authors suggested that these nanocomposites could be used for water disinfection and for medical and pharmaceutical applications [63]. Several reports showed that Si nanowires could interface with the living cells and bacteria interrupting cell functions such as cell differentiation, adhesion and spreading. Lee et al. investigated the antibacterial activity of Ag nanoparticles–Si nanowires. Their results demonstrated high antibacterial activity for these nanostructures. They also indicated that, these nanostructures were biocompatible with the human lung adenocarcinoma epithelial cell line A549 [13,64]. Fellahi et al. reported the preparation and evaluation of antibacterial activity of Si nanowire substrates decorated with Ag or Cu nanoparticles. According to the authors, their prepared nanoparticles revealed strong antibacterial activity against E. coli. Ag decorated Si nanowires found to be biocompatible with human lung adenocarcinoma epithelial cell line A549 while Cu decorated Si nanowires showed high cytotoxicity [13]. All of these studies signify that development of Si compounds and composites especially their nanocomposites together with metals such as Ag shows great potential on the development of antimicrobial agents. In addition, non-toxicity of Si nanoparticles offers their use as antimicrobial agents in the biomedical applications. 7. MgO and CaO nanoparticles CaO and MgO indicate strong antibacterial activity related to alkalinity and active oxygen species. It has been verified that the antibacterial
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mechanism of CaO and MgO nanoparticles is brought about by the generation of superoxide on the surface of these particles, and also an increase in pH value by the hydration of CaO and MgO with water [65]. According to the reports, MgO nanoparticles damage the cell membrane and then cause the leakage of intracellular contents which in turn lead to death of the bacterial cells [66]. Hewitt et al. reported that MgO initiated the sensitivity changes in E. coli induced by active oxygen [67]. However, Leung et al. described that strong antibacterial activity of the MgO nanoparticles could be observed in the absence of any ROS production. They declared that the mechanism of antimicrobial activity might be due to the cell membrane damage [68]. MgO nanoparticles showed the bactericidal activity against both Gram-positive and Gram-negative bacteria [69]. Sawai et al. investigated antibacterial activity of MgO against E. coli or S. aureus. They suggested that the presence of active oxygen, such as superoxide, on the surfaces of MgO nanoparticles was one of the primary factors that affects their antibacterial activity [71]. Jin and He also evaluated antibacterial activities of MgO nanoparticles alone or in combination with other antimicrobials (nisin and ZnO nanoparticles) against E. coli and Salmonella Stanley. MgO nanoparticles showed strong bactericidal activity against these pathogens (more than 7 log reductions in bacterial counts). In their work, the antibacterial activity of MgO nanoparticles was improved as the concentrations of MgO increased. The authors suggested that MgO nanoparticles alone or in combination with nisin could be utilized as an effective antibacterial agent to enhance food safety [66]. Jeong et al. investigated the antimicrobial efficiency of CaCO3 nanoparticles. According to their results, CaCO3 converted to CaO as a result of heat treatment. CaO nanoparticles showed bactericidal activity against E. coli, S. typhimurium, S. aureus and B. subtilis [70]. Yamamoto et al. examined antibacterial activity of CaCO3/MgO nanocomposites against Gram-positive (S. aureus) and Gram-negative (E. coli) bacteria. Their results exhibited superior antibacterial action against S. aureus than E. coli. According to the authors, the mechanism of antibacterial effect of CaO and MgO was due to the generation of superoxide on their surface and also an increase in pH value by the hydration of CaO and MgO with water [65]. Vidic et al. evaluated antimicrobial activity of mixed nanostructure of ZnO–MgO. They also compared antimicrobial activity of ZnO–MgO nanoparticles with pure ZnO and MgO nanoparticles. According to their findings, ZnO nanocrystals showed the high antimicrobial activity against both Gram-positive (B. subtilis) and Gram-negative (E. coli). MgO nanoparticles revealed moderate activity and ZnO–MgO nanoparticles indicated high antibacterial activity against Gram-positive bacteria. Their microscopic analysis showed that B. subtilis cells were damaged after contact with ZnO–MgO nanoparticles. They suggested that nanostructured ZnO–MgO could be used as a safe new therapeutic for bacterial infections [69]. Mentioned results indicated that, MgO and CaO nanoparticles alone or in combination with other disinfectants show excellent antibacterial effect. These nanoparticles also are low cost, biocompatible and available materials. These properties make them promising antibacterial agent [68]. Researchers suggested that, these materials can be utilized in environmental preservation as well as in food processing and medical treatments [72]. 8. Cu and CuO nanoparticles Cu nanoparticles due to their unique biological, chemical and physical properties, antimicrobial activities as well as the low cost of preparation are of great interest to the scientists [73–75]. Usman et al. investigated the antimicrobial activities of Cu-chitosan nanoparticles (2–350 nm). They evaluated antibacterial and antifungal activities of these nanoparticles on several microorganisms, including methicillinresistant S. aureus, B. subtilis, P. aeruginosa, Salmonella choleraesuis, and
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Fig. 1. Various mechanisms of antimicrobial activity of the metal nanoparticles.
C. albicans. Their results indicated the high potential of these nanoparticles as antimicrobial agents [74]. However, rapid oxidation of the Cu nanoparticles on exposure to the air limits their application [74,76]. Mahapatra et al. tested antibacterial activity of CuO nanoparticles against Klebsiella pneumoniae, P. aeruginosa, Salmonella paratyphi and Shigella strains. According to their report, these nanoparticles indicated suitable antibacterial activity against the mentioned bacteria. The authors believed that crossing of nanoparticles through the bacterial cell membrane and then damaging the vital enzymes of bacteria were the critical factors that trigger cell death. They also indicated that these nanoparticles were not cytotoxic on HeLa cell line [76]. Azam et al. reported size-dependent antibacterial activity of CuO nanoparticles. They investigated the antibacterial activities of CuO nanoparticles against two Gram-positive bacteria (S. aureus and
B. subtilis) and two Gram-negative bacteria (Pseudomonas aeruginosa and E. coli). According to their results, CuO nanoparticles exhibited inhibitory effects against both groups of the mentioned bacteria. The authors concluded that bactericidal activity of these nanoparticles depended on their size, stability, and concentration added to the growth medium. The authors stated that, the metal nanoparticles restrict bacterial growth via passing through nanometric pores exist on the cellular membranes of most bacteria [77]. Ahamed et al.'s studies revealed that CuO nanoparticles (23 nm) had significant antimicrobial activity against various bacterial strains (E. coli, P. aeruginosa, K. pneumoniae, Enterococcus faecalis, Shigella flexneri, S. typhimurium, Proteus vulgaris, and S. aureus). Among these pathogens, E. coli and E. faecalis showed the highest sensitivity to CuO nanoparticles while K. pneumoniae was almost resistant to these nano formulations [75].
Table 1 Commonly used nanometals as antimicrobial agent, their mechanisms of action and characteristics. Type of the nanoparticles
Proposed mechanism of antimicrobial action
Main characteristics as antimicrobial agent
The main factors that influence antimicrobial activity
Reference
Ag nanoparticles
Ion release; induction of pits and gaps in the bacterial membrane; interact with disulfide or sulfhydryl groups of enzymes that lead to disruption of metabolic processes. DNA loses its replication ability and the cell cycle halts at the G2/M phase owing to the DNA damage (in the case of Ag2O). ROS generation on the surface of the particles; zinc ion release, membrane dysfunction; and nanoparticles internalization into cell.
High antimicrobial activity against both bacteria and drug-resistant bacteria, antifungal activity on spore-producing fungal plant pathogens, high stability, nontoxicity.
Particle size and shape of particles.
[8,15,22,25,26]
Photocatalytic activity; high stability; bactericidal effects on both Gram-positive and Gram-negative bacteria; antibacterial activity against spores which are resistant to high temperature and high pressure. Suitable photocatalytic properties; high stability; effective antifungal for fluconazole resistant strains.
Particle size and concentration.
[10,34–36,44,50]
Crystal structure, shape and size.
[1,44,51–53]
Nontoxicity, not inducing any ROS-related process; high ability to functionalization, polyvalent effects; ease of detection; photothermal activity.
Roughness and particle size.
[54,55,57,58]
Non-toxicity; stability.
Particle size and shape.
[52,61,63,65]
Effective against Gram-positive and Gram-negative bacteria; high stability; antifungal activity. Effective against both Gram-positive and Gram-negative bacteria; high stability; low cost; availability.
Particle size and concentration.
[36,75,76]
Particle size, pH and concentration.
[65–69]
ZnO nanoparticles
TiO2 nanoparticles
Au nanoparticles
Si nanoparticles CuO nanoparticles
MgO and CaO nanoparticles
Oxidative stress via the generation of ROS; lipid peroxidation that cause to enhance membrane fluidity and disrupt the cell integrity. Attachment of these nanoparticles to membrane which change the membrane potential and then cause the decrease the ATP level; and inhibition of tRNA binding to the ribosome Influencing the cell functions such as cell differentiation, adhesion and spreading. Crossing of nanoparticles from the bacteria cell membrane and then damaging the vital enzymes of bacteria. Damaging the cell membrane and then causing the leakage of intracellular contents and death of the bacterial cells.
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As a final point, there are several proposed mechanisms in respect to antimicrobial activities of the metal nanoparticles. Fig. 1 shows the different proposed antimicrobial mechanisms of the nanometals. The common nanometals used as antimicrobial agents together with their mechanisms of action are summarized in Table 1 as well. 9. Conclusion Due to ever-increasing microbial resistance to the common disinfectants and antibiotics, numerous studies have been performed to improve antimicrobial strategies. Several valuable studies have been documented in the field of antibacterial nanoparticles in the recent years. Application of metal and metal oxide nanoparticles could be considered as a suitable alternative for some antimicrobial methods. The antimicrobial nanoparticles could be benefitted in the pharmaceutical and biomedical industries for sterilization of the medical devices. These nanostructures could also be directed for preparation of chemical disinfectants, coating-based applications and food preparation processes. Metal nanoparticles (especially metal oxide nanoparticles) show great antimicrobial effects. Improved effectiveness of the metal oxide nanoparticles on the resistant strains of microbial pathogens as well as their heat resistance offer them as potent antimicrobial agents. However, application of some of the metal oxide nanoparticles is limited because of their toxicity at higher concentrations. It has also proposed that functionalization; ion doping and polymer conjugates of these nanoparticles could be helpful to decrease the associated toxicity. Finally it may be concluded that, the metal oxide nanoparticles with the minimized toxicity possibly will be extensively used in the near future for eradicating several infectious conditions. We believe that development of the simple and low cost inorganic antimicrobial agents such as metal and metal oxide nanoparticles as alternative of traditional antibiotics might be promising for future of pharmaceutics and medicine. References [1] A.M. Allahverdiyev, E.S. Abamor, M. Bagirova, M. Rafailovich, Antimicrobial effects of TiO2 and Ag2O nanoparticles against drug-resistant bacteria and leishmania parasites, Future Microbiol 6 (2011) 933–940. [2] C. Malarkodi, S. Rajeshkumar, K. Paulkumar, M. Vanaja, G. Gnanajobitha, G. Annadurai, Biosynthesis and Antimicrobial Activity of Semiconductor Nanoparticles against Oral Pathogens, Bioinorg. Chem. Appl. 2014 (2014) 1–10. [3] K. Adibkia, Y. Omidi, M.R. Siahi, A.R. Javadzadeh, M. Barzegar-Jalali, J. Barar, N. Maleki, G. Mohammadi, A. Nokhodchi, Inhibition of endotoxin-induced uveitis by methylprednisolone acetate nanosuspension in rabbits, J. Ocul. Pharmacol. Ther. 23 (2007) 421–432. [4] K. Adibkia, Y. Javadzadeh, S. Dastmalchi, G. Mohammadi, F.K. Niri, M. Alaei-Beirami, Naproxen–eudragit RS100 nanoparticles: Preparation and physicochemical characterization, Colloids Surf. B 83 (2011) 155–159. [5] A. Sabzevari, K. Adibkia, H. Hashemi, A. Hedayatfar, N. Mohsenzadeh, F. Atyabi, M.H. Ghahremani, R. Dinarvand, Polymeric triamcinolone acetonide nanoparticles as a new alternative in the treatment of uveitis: In vitro and in vivo studies, Eur. J. Pharm. Biopharm. 84 (2013) 63–71. [6] J.T. Seil, T.J. Webster, Antimicrobial applications of nanotechnology: methods and literature, Int. J. Nanomedicine 7 (2012) 2767–2781. [7] K. Adibkia, M. Alaei-Beirami, M. Barzegar-Jalali, G. Mohammadi, M.S. Ardestani, Evaluation and optimization of factors affecting novel diclofenac sodium-eudragit RS100 nanoparticles, Afr. J. Pharm. Pharmacol. 6 (2012) 941–947. [8] C. Buzea, I.I. Pacheco, K. Robbie, Nanomaterials and nanoparticles: sources and toxicity, Biointerphases 2 (2007) MR17–MR71. [9] K. Adibkia, M. Barzegar-Jalali, A. Nokhodchi, M. Siahi Shadbad, Y. Omidi, Y. Javadzadeh, G. Mohammadi, A review on the methods of preparation of pharmaceutical nanoparticles, J. Pharm. Sci. 15 (2010) 303–314. [10] V. Ravishankar Rai, A. Jamuna Bai, Nanoparticles and their potential application as antimicrobials, Science Against Microbial Pathogens: Communicating Current Research and Technological Advances2011. 197–209. [11] A. Besinis, T. De Peralta, R.D. Handy, The antibacterial effects of silver, titanium dioxide and silica dioxide nanoparticles compared to the dental disinfectant chlorhexidine on Streptococcus mutans using a suite of bioassays, Nanotoxicology 8 (2014) 1–16. [12] G. Mohammadi, H. Valizadeh, M. Barzegar-Jalali, F. Lotfipour, K. Adibkia, M. Milani, M. Azhdarzadeh, F. Kiafar, A. Nokhodchi, Development of azithromycin–PLGA nanoparticles: Physicochemical characterization and antibacterial effect against Salmonella typhi, Colloids Surf. B 80 (2010) 34–39. [13] O. Fellahi, R.K. Sarma, M.R. Das, R. Saikia, L. Marcon, Y. Coffinier, T. Hadjersi, M. Maamache, R. Boukherroub, The antimicrobial effect of silicon nanowires decorated with silver and copper nanoparticles, Nanotechnology 24 (2013) 495101.
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Contents lists available at ScienceDirect
Materials Science and Engineering C journal homepage: www.elsevier.com/locate/msec
Review
Antimicrobial activity of the metals and metal oxide nanoparticles Solmaz Maleki Dizaj a, Farzaneh Lotfipour a, Mohammad Barzegar-Jalali a, Mohammad Hossein Zarrintan a, Khosro Adibkia b,⁎ a b
Drug Applied Research Center and Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran Biotechnology Research Center and Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
a r t i c l e
i n f o
a b s t r a c t
Article history: Received 7 May 2014 Received in revised form 5 July 2014 Accepted 8 August 2014 Available online 16 August 2014
The ever increasing resistance of pathogens towards antibiotics has caused serious health problems in the recent years. It has been shown that by combining modern technologies such as nanotechnology and material science with intrinsic antimicrobial activity of the metals, novel applications for these substances could be identified. According to the reports, metal and metal oxide nanoparticles represent a group of materials which were investigated in respect to their antimicrobial effects. In the present review, we focused on the recent research works concerning antimicrobial activity of metal and metal oxide nanoparticles together with their mechanism of action. Reviewed literature indicated that the particle size was the essential parameter which determined the antimicrobial effectiveness of the metal nanoparticles. Combination therapy with the metal nanoparticles might be one of the possible strategies to overcome the current bacterial resistance to the antibacterial agents. However, further studies should be performed to minimize the toxicity of metal and metal oxide nanoparticles to apply as proper alternatives for antibiotics and disinfectants especially in biomedical applications. © 2014 Elsevier B.V. All rights reserved.
Keywords: Antimicrobial activity Metal nanoparticles Metal oxide nanoparticles Reactive oxygen species
Contents 1. Introduction . . . . . . . 2. Ag and Ag2O nanoparticles 3. ZnO nanoparticles . . . . 4. TiO2 nanoparticles . . . . 5. Au nanoparticles . . . . . 6. Si and SiO2 nanoparticles . 7. MgO and CaO nanoparticles 8. Cu and CuO nanoparticles . 9. Conclusion . . . . . . . . References . . . . . . . . . .
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1. Introduction Emergence of the antibiotic resistance pathogens has become a serious health issue and thus, numerous studies have been reported to improve the current antimicrobial therapies. It is known that over 70% of bacterial infections are resistant to one or more of the antibiotics that are generally used to eradicate the infection [1]. Development of ⁎ Corresponding author at: Faculty of Pharmacy, Tabriz University of Medical Sciences, Golgasht Street, Daneshgah Ave., Tabriz, Iran. Tel.: +98 411 3341315; fax: + 98 411 3344798. E-mail address: [email protected] (K. Adibkia).
http://dx.doi.org/10.1016/j.msec.2014.08.031 0928-4931/© 2014 Elsevier B.V. All rights reserved.
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new and effective antimicrobial agents seems to be of paramount importance. The antimicrobial activity of metals such as silver (Ag), copper (Cu), gold (Au), titanium (Ti), and zinc (Zn), each having various properties, potencies and spectra of activity, has been known and applied for centuries [2]. Recently, nanotechnology has offered great possibilities in various fields of science and technology. Pharmaceutical nanotechnology with numerous advantages has growingly attracted the attention of many researchers [3]. The application of nanomaterials in the drug delivery systems has been investigated for more than twenty years bringing about innovation of dosage forms with improved therapeutic effects and physicochemical characteristics [4,5]. Several types of nanoparticles
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and their derivatives have received great attention for their potential antimicrobial effects. Metal nanoparticles such as Ag, silver oxide (Ag2O), titanium dioxide (TiO2), silicon (Si), copper oxide (CuO), zinc oxide (ZnO), Au, calcium oxide (CaO) and magnesium oxide (MgO) were identified to exhibit antimicrobial activity. In vitro studies revealed that metal nanoparticles inhibited several microbial species. The kind of the materials used for preparing the nanoparticles as well as the particle size were two important parameters that affected the resultant antimicrobial effectiveness [6,7]. Generally nanoparticles have different properties compared to the same material with the larger particles owing to the fact that the surface/volume ratio of the nanoparticles increases considerably with decrease in the particle size [8,9]. Indeed, in the nanometer dimensions, fraction of the surface molecule is noticeably increased which in turn improves some properties of the particles e.g. heat treatment, mass transfer, dissolution rate, catalytic activity [8,10]. The exact mechanisms for antibacterial effect of nanometals are still being investigated, but there are two more popular proposed possibilities in this regard: (a), free metal ion toxicity arising from dissolution of the metals from surface of the nanoparticles and (b), oxidative stress via the generation of reactive oxygen species (ROS) on surfaces of the nanoparticles [11]. Furthermore, morphological and physicochemical characteristics of the nanometals have been proven to exert an effect on their antimicrobial activities [6,12]. It is known that the small nanoparticles have the strongest bactericidal effect [8,11,13,14]. The positive surface charge of the metal nanoparticles facilitates their binding to the negatively charged surface of the bacteria which may result in an enhancement of the bactericidal effect [6]. The shape of the nanoparticles also influences their antimicrobial effects [15,16]. In this article, we focused on the latest findings about antimicrobial activity of the most commonly employed nanometals and their mechanism of action. Owing to the promising development and the vast application of nanoparticles, understanding the nanotoxicity and its outcomes is necessary. For years, pharmaceutical sciences have used nanoparticles to reduce toxicity and side effects of the drugs; nevertheless, there are some safety concerns about the nanoparticles. According to the reports, neurological and respiratory damage, circulatory problems and some other toxicity effect of nanoparticles are the main concerns in use of the nanoparticles [17–19]. Indeed, several types of the nanoparticles appear to be non-toxic and some of them are rendered non-toxic with beneficial health effects [20]. Appling antimicrobial activity of the nanoparticles to eradicate bacterial infections could be considered as one of these valuable health issues. 2. Ag and Ag2O nanoparticles According to literature Ag nanoparticles are the most popular inorganic nanoparticles used as antimicrobial agents [21]. The antimicrobial application of Ag additives is widely benefitted in the various injectionmolded plastic products, textiles and coating-based usages [22]. Ag nanoparticles also possess a range of biomedical applications [2]. It has been revealed that, Ag nanoparticles show a high antimicrobial activity comparable with its ionic form [23]. It has also been demonstrated that Ag nanoparticles are potential antimicrobial agents against drugresistant bacteria [1]. According to literature, antibacterial action of Ag nanoparticles results from damage of the bacterial outer membrane [24]. Some researchers suppose that, Ag nanoparticles can induce pits and gaps in the bacterial membrane and then fragment the cell [25, 26]. It has also been known that Ag ions interact with disulfide or sulfhydryl groups of enzymes that lead to disruption of metabolic processes which in turn cause the cell death [22]. Jo et al. investigated the effect of size reduction on the antimicrobial effect of Ag nanoparticles. They used Ag nanoparticles to control Bipolaris-sor Okiniana and Magnaporthe Grisea. Similarly, they also evaluated the efficacy of Ag nanoparticles on different types of pathogens
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such as soilborne fungi which rarely produce spores. According to their results, Ag nanoparticles (20 to 30 nm) could better penetrate and colonize within the plant tissue. They suggested that, Ag nanoparticles had a great potential for use in controlling spore-producing fungal plant pathogens. They suggested that these nanoparticles might be less toxic than synthetic fungicides [23]. In the other study, Mie and et al. tested the antibacterial activity of their synthesized Ag nanoparticles (19 nm) against eight micro-organisms using the disk diffusion method. Their results revealed that the Ag nanoparticles showed potential antibacterial activity against Gram-negative bacteria. Thus, the authors suggested that these synthesized Ag nanoparticles could be applied in the pharmaceutical and biomedical industries [27]. Hernández-Sierra et al. reported comparative investigation of the bactericidal activity of Ag nanoparticles, ZnO, and Au on Streptococcus mutans (S. mutans). Their results indicated that Ag nanoparticles exhibited the most activity for controlling S. mutans. The authors suggested that Ag nanoparticles could be used in dental caries since it commonly is caused by S. mutans [28]. Likewise, Besinis et al. investigated the antibacterial effect of Ag nanoparticles on S. mutans. Their results showed that the antibacterial effect of Ag nanoparticles against S. mutans was more superior than that of chlorhexidine [11]. Zarei et al. evaluated antibacterial effect of Ag nanoparticles against four foodborne pathogens namely Listeria monocytogenes, Escherichia coli (E. coli), Salmonella typhimurium (S. typhimurium) and Vibrio parahaemolyticus. According to their results, Ag nanoparticles had great antibacterial effect on the mentioned pathogens. They concluded that Ag nanoparticles could be a good alternative for cleaning and disinfection of equipment and surfaces in the food-related environments [29]. Beside the particle size reduction, shape-dependent properties of nanoparticles have also been investigated by researchers. Pal et al. reported the shape dependent antibacterial activity of Ag nanoparticles (in three different forms: spherical, rod-shaped and truncated triangular). According to their findings, truncated triangular nanoparticles were more reactive due to their high-atom-density surfaces, and therefore showed higher antimicrobial activity [15]. In the other study, Bera et al. stated the size and shape-dependent antimicrobial activity of fluorescent Ag nanoparticles (1–5 nm) against Gram-positive (Staphylococcus epidermidis and Bacillus megaterium) and Gram-negative bacteria (Pseudomonas aeruginosa). They emphasized that the shape and size of the particles controlled their activity. According to these investigations, the smaller particles easily penetrated the cell wall and showed the enhanced antimicrobial activity. The authors suggested that these Ag nanoparticles could be used for different purposes such as clinical wound dressing, bioadhesives, biofilms and the coating of biomedical materials [16]. Bahrami prepared Ag–Au alloy nanoparticles to evaluate their antimicrobial effect against Staphylococcus aureus (S. aureus). The antibacterial activity of Ag–Au alloy nanoparticles was intensified when they combined with penicillin G and piperacillin. The authors suggested that Ag–Au alloy nanoparticles could be used as an adjuvant in combination therapy of antibiotics [30]. Ag2O nanoparticles have also been discovered to have great antimicrobial activity [1]. It is believed that, metal oxide nanoparticles might be considered as a novel alternative to the most antibiotics [1,31]. Sondi and Salopek-Sondi demonstrated antimicrobial efficacy of Ag2O nanoparticles against E. coli. They proposed that when E. coli were exposed to these nanoparticles, DNA lost its replication ability and the cell cycle halted at the G2/M phase owing to the DNA damage. Then the cells were affected by oxidative stress, and apoptosis was induced [32]. Furthermore, Ag had reported to be less toxic than many other disinfectants. Marambio-Jones and Hoek had reviewed the antibacterial mechanisms of the Ag nanoparticles and potential implications for human health and environment [33]. We think that further research should be performed to develop Ag compounds, composites and alloys with the minimum toxicity and maximum antimicrobial effect.
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3. ZnO nanoparticles
4. TiO2 nanoparticles
Safety of ZnO and its compatibility with human skin make it a suitable additive for textiles and surfaces that come in contact with the human body [34,35]. ZnO nanoparticles showed bactericidal effects on Gram-positive and Gram-negative bacteria as well as the spores which are resistant to high temperature and high pressure [36]. The improved antibacterial activity of ZnO nanoparticles compared to its microparticles was related to the surface area enhancement in the nanoparticles [6,37,38]. Padmavathy et al. investigated the antibacterial activity of ZnO nanoparticles with various particle sizes. Their results demonstrated that the bactericidal efficacy of ZnO nanoparticles increased by decreasing particle size [38]. Azam et al. reported comparative investigation of antimicrobial activity of ZnO, CuO, and Fe2 O 3 nanoparticles against Gramnegative (E. coli and P. aeruginosa) and Gram-positive (S. aureus and Bacillus subtilis (B. subtilis)) bacteria. According to their results, the most bactericidal activity was reported for the ZnO nanoparticles while Fe2 O3 nanoparticles exhibited the least antibacterial effect [36]. In particular, ZnO reduces the bacteria viability; however, the exact mechanism of its antibacterial activity has not been well understood so far. One proposed possibility is the generation of hydrogen peroxide as a main factor of the antibacterial activity. It is also believed that, the accumulation of the particles on the bacteria surface due to the electrostatic forces could be another mechanism of the antibacterial effect of ZnO particles [39]. Besides, ROS generated on the surface of the particles, zinc ion release, membrane dysfunction, and nanoparticles internalization could also be taken into account as the possible reasons of the cell damage [40]. Moreover, interruption of transmembrane electron transportation has been stated in the case of some metal nanoparticles such as Ag and Zn [41–43]. Xie et al. evaluated antibacterial activity of ZnO nanoparticles against Campylobacter jejuni (C. jejuni). They suggested that the antibacterial mechanism of ZnO nanoparticles might be due to disruption of the cell membrane and oxidative stress in C. jejuni. Their results signified that ZnO nanoparticles caused morphological changes, measurable membrane leakage, and increase (up to 52-fold) in oxidative stress gene expression in C. jejuni [37]. Ag nanoparticles showed antibacterial activity even in the ultra-low concentrations [44]; however, the antibacterial activity of ZnO nanoparticles depended on the concentration and surface area. Thus ZnO nanoparticles in higher concentrations and larger surface area displayed better antibacterial activity [8]. Hossein-khani et al. investigated the antibacterial characteristics of ZnO nanoparticle against Shigella dysenteriae. Based on their results, a considerable decrease in the bacteria number was observed as a result of particles size reduction [45]. Emami-Karvani et al. investigated the antimicrobial activity of ZnO nanoparticles against Gram-negative (E. coli) and Gram-positive (S. aureus) bacteria. They evaluated the effects of concentration and particle size reduction on the antibacterial activity of ZnO nanoparticles. They found that the antibacterial activity of ZnO nanoparticles increased with decreasing particle size and enhancing powder concentration; nonetheless, ZnO bulk powder showed no significant antibacterial activity [46]. Some studies have shown that preparation of metal ion doped nanoparticles can improve antimicrobial properties of metal nanoparticles [47–49]. Sun et al. synthesized the titanium-doped ZnO powders from different zinc salts. Their results showed that the titanium doped ZnO powders had the antibacterial action against E. coli and S. aureus. The authors emphasized that the antibacterial properties of the titaniumdoped ZnO powders were related to the particle size reduction and the crystallinity [48]. Moreover, ZnO nanoparticles exhibit high photocatalytic properties which improve their antimicrobial efficiency [44]. ZnO nanoparticles produce ROS under UV light as well [50].
Antimicrobial property of TiO2 is related to its crystal structure, shape and size [51]. It is proposed that oxidative stress via the generation of ROS may be a particularly important mechanism for TiO2 nanoparticles (anatase forms). Then ROS cause site specific DNA damage [44,52]. Roy et al. evaluated the effect of TiO2 nanoparticles with different antibiotics against methicillin-resistant S. aureus (MRSA). They reprted that, TiO2 nanoparticles improved the antimicrobial effect of beta lactums, cephalosporins, aminoglycosides, glycopeptides, macrolids, lincosamides and tetracycline against MRSA. In another experiment, their results showed that antimicrobial resistance of MRSA against various antibiotics decreased in the presence of TiO2 nanoparticles [52]. Haghighi et al. investigated antifungal effect of TiO2 nanoparticles on the fungal biofilms (fluconazole resistant standard strains of Candida albicans (C. albicans)). According to their results, the synthesized TiO2 nanoparticles had improved antifungal effect on the fluconazole resistant strain of C. albicans biofilms. The authors suggested that TiO2 nanoparticles could effectively inhibit the fungal biofilms especially those formed on the surface of medical devices [51]. Photocatalytic properties of the TiO2 nanoparticles help them to efficiently eradicate the bacteria. In fact, TiO2 nanoparticles produce ROS under UV light. Carré et al. considered that the antibacterial photocatalytic activity was accompanied by lipid peroxidation that causes to enhance membrane fluidity and disrupt the cell integrity [53]. However, the use of TiO2 nanoparticles under UV light is restricted because of genetic damage in human cells and tissues [1]. It has been proved that, doping of TiO2 nanoparticles with metal ions can be a good idea to overcome this problem. In addition, antibacterial and photocatalytic properties of TiO2 nanoparticles are significantly enhanced by doping them with metal ions [1,47]. In other words, doping with metal ions shifts TiO2 nanoparticles' light absorption range to visible light and therefore, there is no need to irradiate them with UV light [1]. Conjugation of TiO2 nanoparticles with nontoxic polymers is another approach to overcome toxicity problems of TiO2 nanoparticles. For instance, Rafailovich et al. reported that TiO2 nanoparticles–polymer conjugates were harmless to fibroblast cells [1]. 5. Au nanoparticles Au nanoparticles are considered to be so valuable in the development of antibacterial agents due to their nontoxicity, high ability to functionalization, polyvalent effects, ease of detection and photothermal activity [54–57]. Although generation of ROS is the main cause of cellular death for most antibiotics and antibacterial nanomaterials; nevertheless, antimicrobial activity of Au nanoparticles do not induce any ROS-related process [58]. Cui et al. proved that antibacterial activity of the Au nanoparticles was attributable to 1) attachment of these nanoparticles to the bacterial membrane followed by membrane potential modification and ATP level decrease and 2) inhibition of tRNA binding to the ribosome [58]. Tiwari et al. investigated the antibacterial and antifungal activities of the Au nanoparticles functionalized with 5-fluorouracil against Micrococcus luteus, S. aureus, P. aeruginosa, E. coli, Aspergillus fumigates (A. fumigates), and Aspergillus niger (A. niger). The authors reported that these nanoparticles showed more activity on Gram negative bacteria than Gram positive ones due to their easier internalization into the Gram negative bacteria. These nanoparticles indicated antifungal activity against A. fumigates and A. niger as well [55]. Zhou et al. tested antibacterial activities of Au and Ag nanoparticles against E. coli and bacillus Calmette-Guérin (BCG). They claimed that, Au and Ag nanoparticles exhibited significant antibacterial activity against both Gram negative (E. coli) and the Gram positive bacteria (BCG). They also functionalized Au nanoparticles with a strongly bound capping (poly-allylamine hydrochloride) and a weakly bound
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capping agent (citrate). Poly-allylamine hydrochloride could directly contact with the bacterial cell membrane due to its positively charged nature [59]. Furthermore, Au nanoparticles functionalized with strongly bound capping agents could self-assemble into 4–5 μm long chains [60]. Zhou et al. explained that these two mentioned processes facilitate the delivery of a large number of Au nanoparticles on the bacterial cell wall. Conversely, extra-aggregation of weakly bound capping agents like citrate causes reduced surface area and so decreased interactions with the nanoparticles. Accordingly, Au nanoparticle with the same shape and size but different capping agent exhibits different antimicrobial activities [56]. In another study, Lima et al. reported antimicrobial effect of Au nanoparticles (5 nm) against E. coli and Salmonella typhi (S. typhi) bacteria. Their results showed that, these nanoparticles reduced 90–95% of E. coli and S. typhi colonies. The authors emphasized that, the main factors that influenced the biocidal properties were the roughness and the dispersion of the Au nanoparticles on the medium [54]. It seems that Au nanoparticles are safer to the mammalian cells than the other nanometals due to the ROS-independent mechanism of their antimicrobial activity. Moreover, high ability of these nanoparticles for functionalization makes them ideal nanomaterials to be applied as targeted antimicrobial agents. 6. Si and SiO2 nanoparticles Antimicrobial activity of SiO2 would become more significant at nano-scale owing to the increased surface area [61]. Cousins et al. found that Si nanoparticles inhibited bacterial adherence to oral biofilms [62]. Combination use of Si nanoparticles with the other biocidal metals such as Ag has been extensively studied in the recent years. Egger et al. reported the production and investigation of antimicrobial activity of novel Ag–Si nanocomposite. Their results revealed better antimicrobial effect of the nanocomposite against a wide range of microorganisms compared to conventional materials, such as silver nitrate and silver zeolite [22]. In the other study, Mukha et al. synthesized Ag/SiO2 and Au/SiO2 nanostructures and investigated their antimicrobial activity. The results showed that Ag/SiO2 nanocomposites indicated improved antimicrobial properties against E. coli, S. aureus, and C. albicans while Au/SiO2 nanocomposites did not show any antibacterial activity against the mentioned microorganisms. The authors suggested that these nanocomposites could be used for water disinfection and for medical and pharmaceutical applications [63]. Several reports showed that Si nanowires could interface with the living cells and bacteria interrupting cell functions such as cell differentiation, adhesion and spreading. Lee et al. investigated the antibacterial activity of Ag nanoparticles–Si nanowires. Their results demonstrated high antibacterial activity for these nanostructures. They also indicated that, these nanostructures were biocompatible with the human lung adenocarcinoma epithelial cell line A549 [13,64]. Fellahi et al. reported the preparation and evaluation of antibacterial activity of Si nanowire substrates decorated with Ag or Cu nanoparticles. According to the authors, their prepared nanoparticles revealed strong antibacterial activity against E. coli. Ag decorated Si nanowires found to be biocompatible with human lung adenocarcinoma epithelial cell line A549 while Cu decorated Si nanowires showed high cytotoxicity [13]. All of these studies signify that development of Si compounds and composites especially their nanocomposites together with metals such as Ag shows great potential on the development of antimicrobial agents. In addition, non-toxicity of Si nanoparticles offers their use as antimicrobial agents in the biomedical applications. 7. MgO and CaO nanoparticles CaO and MgO indicate strong antibacterial activity related to alkalinity and active oxygen species. It has been verified that the antibacterial
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mechanism of CaO and MgO nanoparticles is brought about by the generation of superoxide on the surface of these particles, and also an increase in pH value by the hydration of CaO and MgO with water [65]. According to the reports, MgO nanoparticles damage the cell membrane and then cause the leakage of intracellular contents which in turn lead to death of the bacterial cells [66]. Hewitt et al. reported that MgO initiated the sensitivity changes in E. coli induced by active oxygen [67]. However, Leung et al. described that strong antibacterial activity of the MgO nanoparticles could be observed in the absence of any ROS production. They declared that the mechanism of antimicrobial activity might be due to the cell membrane damage [68]. MgO nanoparticles showed the bactericidal activity against both Gram-positive and Gram-negative bacteria [69]. Sawai et al. investigated antibacterial activity of MgO against E. coli or S. aureus. They suggested that the presence of active oxygen, such as superoxide, on the surfaces of MgO nanoparticles was one of the primary factors that affects their antibacterial activity [71]. Jin and He also evaluated antibacterial activities of MgO nanoparticles alone or in combination with other antimicrobials (nisin and ZnO nanoparticles) against E. coli and Salmonella Stanley. MgO nanoparticles showed strong bactericidal activity against these pathogens (more than 7 log reductions in bacterial counts). In their work, the antibacterial activity of MgO nanoparticles was improved as the concentrations of MgO increased. The authors suggested that MgO nanoparticles alone or in combination with nisin could be utilized as an effective antibacterial agent to enhance food safety [66]. Jeong et al. investigated the antimicrobial efficiency of CaCO3 nanoparticles. According to their results, CaCO3 converted to CaO as a result of heat treatment. CaO nanoparticles showed bactericidal activity against E. coli, S. typhimurium, S. aureus and B. subtilis [70]. Yamamoto et al. examined antibacterial activity of CaCO3/MgO nanocomposites against Gram-positive (S. aureus) and Gram-negative (E. coli) bacteria. Their results exhibited superior antibacterial action against S. aureus than E. coli. According to the authors, the mechanism of antibacterial effect of CaO and MgO was due to the generation of superoxide on their surface and also an increase in pH value by the hydration of CaO and MgO with water [65]. Vidic et al. evaluated antimicrobial activity of mixed nanostructure of ZnO–MgO. They also compared antimicrobial activity of ZnO–MgO nanoparticles with pure ZnO and MgO nanoparticles. According to their findings, ZnO nanocrystals showed the high antimicrobial activity against both Gram-positive (B. subtilis) and Gram-negative (E. coli). MgO nanoparticles revealed moderate activity and ZnO–MgO nanoparticles indicated high antibacterial activity against Gram-positive bacteria. Their microscopic analysis showed that B. subtilis cells were damaged after contact with ZnO–MgO nanoparticles. They suggested that nanostructured ZnO–MgO could be used as a safe new therapeutic for bacterial infections [69]. Mentioned results indicated that, MgO and CaO nanoparticles alone or in combination with other disinfectants show excellent antibacterial effect. These nanoparticles also are low cost, biocompatible and available materials. These properties make them promising antibacterial agent [68]. Researchers suggested that, these materials can be utilized in environmental preservation as well as in food processing and medical treatments [72]. 8. Cu and CuO nanoparticles Cu nanoparticles due to their unique biological, chemical and physical properties, antimicrobial activities as well as the low cost of preparation are of great interest to the scientists [73–75]. Usman et al. investigated the antimicrobial activities of Cu-chitosan nanoparticles (2–350 nm). They evaluated antibacterial and antifungal activities of these nanoparticles on several microorganisms, including methicillinresistant S. aureus, B. subtilis, P. aeruginosa, Salmonella choleraesuis, and
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Fig. 1. Various mechanisms of antimicrobial activity of the metal nanoparticles.
C. albicans. Their results indicated the high potential of these nanoparticles as antimicrobial agents [74]. However, rapid oxidation of the Cu nanoparticles on exposure to the air limits their application [74,76]. Mahapatra et al. tested antibacterial activity of CuO nanoparticles against Klebsiella pneumoniae, P. aeruginosa, Salmonella paratyphi and Shigella strains. According to their report, these nanoparticles indicated suitable antibacterial activity against the mentioned bacteria. The authors believed that crossing of nanoparticles through the bacterial cell membrane and then damaging the vital enzymes of bacteria were the critical factors that trigger cell death. They also indicated that these nanoparticles were not cytotoxic on HeLa cell line [76]. Azam et al. reported size-dependent antibacterial activity of CuO nanoparticles. They investigated the antibacterial activities of CuO nanoparticles against two Gram-positive bacteria (S. aureus and
B. subtilis) and two Gram-negative bacteria (Pseudomonas aeruginosa and E. coli). According to their results, CuO nanoparticles exhibited inhibitory effects against both groups of the mentioned bacteria. The authors concluded that bactericidal activity of these nanoparticles depended on their size, stability, and concentration added to the growth medium. The authors stated that, the metal nanoparticles restrict bacterial growth via passing through nanometric pores exist on the cellular membranes of most bacteria [77]. Ahamed et al.'s studies revealed that CuO nanoparticles (23 nm) had significant antimicrobial activity against various bacterial strains (E. coli, P. aeruginosa, K. pneumoniae, Enterococcus faecalis, Shigella flexneri, S. typhimurium, Proteus vulgaris, and S. aureus). Among these pathogens, E. coli and E. faecalis showed the highest sensitivity to CuO nanoparticles while K. pneumoniae was almost resistant to these nano formulations [75].
Table 1 Commonly used nanometals as antimicrobial agent, their mechanisms of action and characteristics. Type of the nanoparticles
Proposed mechanism of antimicrobial action
Main characteristics as antimicrobial agent
The main factors that influence antimicrobial activity
Reference
Ag nanoparticles
Ion release; induction of pits and gaps in the bacterial membrane; interact with disulfide or sulfhydryl groups of enzymes that lead to disruption of metabolic processes. DNA loses its replication ability and the cell cycle halts at the G2/M phase owing to the DNA damage (in the case of Ag2O). ROS generation on the surface of the particles; zinc ion release, membrane dysfunction; and nanoparticles internalization into cell.
High antimicrobial activity against both bacteria and drug-resistant bacteria, antifungal activity on spore-producing fungal plant pathogens, high stability, nontoxicity.
Particle size and shape of particles.
[8,15,22,25,26]
Photocatalytic activity; high stability; bactericidal effects on both Gram-positive and Gram-negative bacteria; antibacterial activity against spores which are resistant to high temperature and high pressure. Suitable photocatalytic properties; high stability; effective antifungal for fluconazole resistant strains.
Particle size and concentration.
[10,34–36,44,50]
Crystal structure, shape and size.
[1,44,51–53]
Nontoxicity, not inducing any ROS-related process; high ability to functionalization, polyvalent effects; ease of detection; photothermal activity.
Roughness and particle size.
[54,55,57,58]
Non-toxicity; stability.
Particle size and shape.
[52,61,63,65]
Effective against Gram-positive and Gram-negative bacteria; high stability; antifungal activity. Effective against both Gram-positive and Gram-negative bacteria; high stability; low cost; availability.
Particle size and concentration.
[36,75,76]
Particle size, pH and concentration.
[65–69]
ZnO nanoparticles
TiO2 nanoparticles
Au nanoparticles
Si nanoparticles CuO nanoparticles
MgO and CaO nanoparticles
Oxidative stress via the generation of ROS; lipid peroxidation that cause to enhance membrane fluidity and disrupt the cell integrity. Attachment of these nanoparticles to membrane which change the membrane potential and then cause the decrease the ATP level; and inhibition of tRNA binding to the ribosome Influencing the cell functions such as cell differentiation, adhesion and spreading. Crossing of nanoparticles from the bacteria cell membrane and then damaging the vital enzymes of bacteria. Damaging the cell membrane and then causing the leakage of intracellular contents and death of the bacterial cells.
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As a final point, there are several proposed mechanisms in respect to antimicrobial activities of the metal nanoparticles. Fig. 1 shows the different proposed antimicrobial mechanisms of the nanometals. The common nanometals used as antimicrobial agents together with their mechanisms of action are summarized in Table 1 as well. 9. Conclusion Due to ever-increasing microbial resistance to the common disinfectants and antibiotics, numerous studies have been performed to improve antimicrobial strategies. Several valuable studies have been documented in the field of antibacterial nanoparticles in the recent years. Application of metal and metal oxide nanoparticles could be considered as a suitable alternative for some antimicrobial methods. The antimicrobial nanoparticles could be benefitted in the pharmaceutical and biomedical industries for sterilization of the medical devices. These nanostructures could also be directed for preparation of chemical disinfectants, coating-based applications and food preparation processes. Metal nanoparticles (especially metal oxide nanoparticles) show great antimicrobial effects. Improved effectiveness of the metal oxide nanoparticles on the resistant strains of microbial pathogens as well as their heat resistance offer them as potent antimicrobial agents. However, application of some of the metal oxide nanoparticles is limited because of their toxicity at higher concentrations. It has also proposed that functionalization; ion doping and polymer conjugates of these nanoparticles could be helpful to decrease the associated toxicity. Finally it may be concluded that, the metal oxide nanoparticles with the minimized toxicity possibly will be extensively used in the near future for eradicating several infectious conditions. We believe that development of the simple and low cost inorganic antimicrobial agents such as metal and metal oxide nanoparticles as alternative of traditional antibiotics might be promising for future of pharmaceutics and medicine. References [1] A.M. Allahverdiyev, E.S. Abamor, M. Bagirova, M. Rafailovich, Antimicrobial effects of TiO2 and Ag2O nanoparticles against drug-resistant bacteria and leishmania parasites, Future Microbiol 6 (2011) 933–940. [2] C. Malarkodi, S. Rajeshkumar, K. Paulkumar, M. Vanaja, G. Gnanajobitha, G. Annadurai, Biosynthesis and Antimicrobial Activity of Semiconductor Nanoparticles against Oral Pathogens, Bioinorg. Chem. Appl. 2014 (2014) 1–10. [3] K. Adibkia, Y. Omidi, M.R. Siahi, A.R. Javadzadeh, M. Barzegar-Jalali, J. Barar, N. Maleki, G. Mohammadi, A. Nokhodchi, Inhibition of endotoxin-induced uveitis by methylprednisolone acetate nanosuspension in rabbits, J. Ocul. Pharmacol. Ther. 23 (2007) 421–432. [4] K. Adibkia, Y. Javadzadeh, S. Dastmalchi, G. Mohammadi, F.K. Niri, M. Alaei-Beirami, Naproxen–eudragit RS100 nanoparticles: Preparation and physicochemical characterization, Colloids Surf. B 83 (2011) 155–159. [5] A. Sabzevari, K. Adibkia, H. Hashemi, A. Hedayatfar, N. Mohsenzadeh, F. Atyabi, M.H. Ghahremani, R. Dinarvand, Polymeric triamcinolone acetonide nanoparticles as a new alternative in the treatment of uveitis: In vitro and in vivo studies, Eur. J. Pharm. Biopharm. 84 (2013) 63–71. [6] J.T. Seil, T.J. Webster, Antimicrobial applications of nanotechnology: methods and literature, Int. J. Nanomedicine 7 (2012) 2767–2781. [7] K. Adibkia, M. Alaei-Beirami, M. Barzegar-Jalali, G. Mohammadi, M.S. Ardestani, Evaluation and optimization of factors affecting novel diclofenac sodium-eudragit RS100 nanoparticles, Afr. J. Pharm. Pharmacol. 6 (2012) 941–947. [8] C. Buzea, I.I. Pacheco, K. Robbie, Nanomaterials and nanoparticles: sources and toxicity, Biointerphases 2 (2007) MR17–MR71. [9] K. Adibkia, M. Barzegar-Jalali, A. Nokhodchi, M. Siahi Shadbad, Y. Omidi, Y. Javadzadeh, G. Mohammadi, A review on the methods of preparation of pharmaceutical nanoparticles, J. Pharm. Sci. 15 (2010) 303–314. [10] V. Ravishankar Rai, A. Jamuna Bai, Nanoparticles and their potential application as antimicrobials, Science Against Microbial Pathogens: Communicating Current Research and Technological Advances2011. 197–209. [11] A. Besinis, T. De Peralta, R.D. Handy, The antibacterial effects of silver, titanium dioxide and silica dioxide nanoparticles compared to the dental disinfectant chlorhexidine on Streptococcus mutans using a suite of bioassays, Nanotoxicology 8 (2014) 1–16. [12] G. Mohammadi, H. Valizadeh, M. Barzegar-Jalali, F. Lotfipour, K. Adibkia, M. Milani, M. Azhdarzadeh, F. Kiafar, A. Nokhodchi, Development of azithromycin–PLGA nanoparticles: Physicochemical characterization and antibacterial effect against Salmonella typhi, Colloids Surf. B 80 (2010) 34–39. [13] O. Fellahi, R.K. Sarma, M.R. Das, R. Saikia, L. Marcon, Y. Coffinier, T. Hadjersi, M. Maamache, R. Boukherroub, The antimicrobial effect of silicon nanowires decorated with silver and copper nanoparticles, Nanotechnology 24 (2013) 495101.
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