Microbial Pathogenesis 123 (2018) 505–526

Contents lists available at ScienceDirect

Microbial Pathogenesis
journal homepage: www.elsevier.com/locate/micpath

Nanoparticles and their antimicrobial properties against pathogens T

including bacteria, fungi, parasites and viruses
Arezou Khezerloua, Mahmood Alizadeh-Sanib, Maryam Azizi-Lalabadib, Ali Ehsanic,∗
a
Talented Students Center, Students Research Committee, Department of Food Sciences and Technology, Faculty of Nutrition and Food Sciences, Tabriz University of
Medical Sciences, Tabriz, Iran
b
Students Research Committee, Department of Food Sciences and Technology, Faculty of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
c
Nutrition Research Center, Department of Food Sciences and Technology, Faculty of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran

A R T I C LE I N FO A B S T R A C T

Keywords: In recent year, propagation and resistance of pathogenic microorganisms (bacteria, fungi and virals) to common
Nanoparticles antimicrobial agents has led to serious health and food problems. Today, nanotechnology science and nano-
Reactive oxygen species particles (NPs) have been identified as a new approach to deal with this problem because of their inherent
Antimicrobial activity antimicrobial activity. Several studies have reported that, NPs (metal and metal oxide) are considered as a group
Pathogenic microorganisms
of materials that can be studied due to their antimicrobial properties. In this review, we investigated recent
Cell toxicity
studies regarding the antimicrobial activity of NPs with their mechanism of action. Many research has proved
that particle size is a significant factor which indicates the antimicrobial effectiveness of NPs. The use of NPs as
antimicrobial component especially in the food additives and medical application can be one of the new and
considerable strategies for overcoming pathogenic microorganisms. Nevertheless, more studies must be con-
ducted to minimize the possible toxicity of NPs in order to use as suitable alternatives for disinfectants and
antibacterial agents in food applications.

1. Introduction mass transfer, dissolution rate and catalytic activity [4,6].

Emergence of pathogenic and spoilage bacteria resistant to anti-
microbial agents has become a serious health issue; thus, many studies
have been accomplished with the aim of improving the current anti-
microbial methods. It is implicated that over 70% of bacterial causing
poisoning and infection are resistant to one or more of the antimicrobial
agents that are generally used for eradicating infection treatment of
poisoning. Development of new and effective antimicrobial agents
seems to be of paramount importance. Metal nanoparticles (NPs) such
as copper (Cu), titanium (Ti), silver (Ag), gold (Au), and zinc (Zn), each
have various antimicrobial activity properties, with potencies and
spectra of activity, which have been known and applied for decades [1].
The type of materials used for preparing NPs as well as particle size
are two important factors affecting resultant antimicrobial efficiency
and effectiveness [2,3]. Generally, NPs have different properties com-
pared to the same material with larger particles. In fact, surface/volume
ratio of NPs increases considerably with decrease in particle size [4,5].
Indeed, in nanometer dimensions, fraction of surface molecule notice-
ably increases which in turn improves factors such as heat treatment,
The exact mechanisms mentioned for the antimicrobial effects of
NPs are still being studied. Up to now two popular possibilities have
been proposed: (a), free metal ion toxicity arising from dissolution of
metals from the surface of NPs (b), oxidative stress via generation of
reactive oxygen species (ROS) on the surface of NPs [7]. Moreover,
morphological and physicochemical characteristics of NPs have been
demonstrated to affect the antimicrobial activities of metals [2,8]. It has
been proven that small NPs have stronger bactericidal effects
[4,7,9,10]. Positive surface charge of metal NPs facilitates their binding
to bacteria with negative surface charge which may result in en-
hancement of bactericidal effects [2]. The shape of NPs also influences
its antimicrobial activities [11,12]. NPs have been proposed as antiviral
agents using the core material and/or the ligands shell [13]. In this
article, we focused on the latest findings regarding antimicrobial effects
of most commonly employed NPs and their mechanism of action. Due
to the promising development and wide application of NPs, under-
standing their non-toxicity and properties is necessary. For this reason,
nanotechnology and pharmaceutical sciences have been used NPs for
reducing the toxicity and side effects of drugs and other material;

∗
Corresponding author. Department of Food Sciences and Technology, Faculty of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Golgasht
Ave, Attar-Neishaboori St., Tabriz, Iran.
E-mail address: ehsani@tbzmed.ac.ir (A. Ehsani).

https://doi.org/10.1016/j.micpath.2018.08.008
Received 26 February 2018; Received in revised form 15 July 2018; Accepted 6 August 2018
Available online 07 August 2018
0882-4010/ © 2018 Elsevier Ltd. All rights reserved.
A. Khezerlou et al. Microbial Pathogenesis 123 (2018) 505–526

Fig. 1. Mechanisms of antimicrobial activity of NPs against pathogens (B). NPs and their ions (e.g., titanium, silver and zinc) generate free radicals, and lead to
induction of oxidative stress (i.e.,ROS) (A). The generated ROS can damage and destroy the cellular components of the pathogens irreversibly, (e.g., membrane, DNA,
protein and mitochondria), resulting in cell death.

nevertheless, there are few safety concerns regarding NPs. According to
reports, respiratory and neurological damage, circulatory problems and
toxic effects of NPs are the main concerns in using NPs [14–16]. Indeed,
several types of NPs are considered non-toxic and some of them are
provided non-toxic with beneficial health effects [17]. Using NPs due to
their antimicrobial activities for overcoming spoilage and pathogenic
microorganisms can be considered as one of these valuable health ap-
proaches.
2. Antimicrobial properties of selected types of NPs
2.1. Titanium dioxide NPs (TiO2)
Antimicrobial activity of TiO2 NPs is attributed to its crystal struc-
ture, size and shape (Fig. 3) [18]. Oxidative stress caused by ROS is
particularly the mechanism proposed for TiO2 NPs. As a result, ROS
cause site specific DNA damage Figs. 1 and 2, [19,20]. Resting stages,
particularly bacterial endospores, fungal spores and protozoan cysts,

506
A. Khezerlou et al.
Fig. 2. Mechanism of photocatalytic activity of Cu/Ag doped TiO2 or ZnO and
producing ROS under irradiation.
are generally more resistant than the vegetative forms, possibly due to
the increased cell wall thickness. The killing mechanism involves de-
gradation of the cell wall and cytoplasmic membrane due to the pro-
duction of reactive oxygen species such as hydroxyl radicals and hy-
drogen peroxide. This initially leads to leakage of cellular contents then
cell lysis and may be followed by complete mineralization of the or-
ganism. The general scheme for the photocatalytic damage of micro-
organism cells by TiO2 photocatalytic properties involves several steps
[21]: (1) the photoexcited TiO2 catalyst produces electron-hole pairs
that migrate to the TiO2 surface; (2) photogenerated holes in TiO2 can
react with adsorbed H2O or OH- at the catalyst/water interface to
produce the highly reactive hydroxyl radicals and the electrons can
react with oxygen vacancies to form superoxide ions; (3) finally, the
various highly active oxygen species generated can oxidize organic
compounds/cells adsorbed on the TiO2 surface, resulting in the death of
the microorganisms. The efficiency of TiO2 photocatalytic properties
and antibacterial activities should depend on our abilities (i) to make
stable nanostructured TiO2 particles or composites, (ii) to generate
electron-hole pairs by extending the excitation wavelength to the
visible light region, and (iii) to achieve a reduced recombination rate on
the newly created electron-hole carriers. Several methods may be used
to improve the photo-catalytic efficiency, including increase of the
surface area of TiO2 through tailoring particle size and pore-size dis-
tributions, generation of defect structures to induce space-charge se-
paration via metal dopants, and surface modification of the TiO2 with a
metal or another semiconductor [22–24].
Fig. 3. Physicochemical properties of the NPs involved in biological activity: size, shape, surface area, chemical composition, surface chemistry, and interactions
between NPs and proteins or receptors that lead to the agglomeration and aggregation in the cell membrane.
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Microbial Pathogenesis 123 (2018) 505–526
Maneerat et al. (2006) were investigated the antifungal activity of
TiO2 photocatalytic reaction in the form of TiO2 powder and TiO2
coated on a plastic film against P. expansum in vitro and in fruit tests.
Their findings suggested that “TiO2 photocatalytic reaction” indicates
antifungal effects against P. expansum which may have potential for
postharvest disease control [25]. Bodaghi et al. (2013) evaluated the
photocatalytic antimicrobial effects of TiO2 nanocomposite LDPE film
on P. spp. and Rhodotorula mucilaginosa. The most effects were reported
by combining UVA illumination and composite LDPE film against tested
bacteria [26]. Roy et al. (2010) investigated the effect of TiO2 NPs
along with different antibiotics against methicillin-resistant S. aureus
(MRSA). They recorded that, TiO2 NPs improve the antimicrobial effect
of different antibiotics against MRSA. In another study, antimicrobial
resistance of MRSA against various antibiotics reduces in the presence
of TiO2 NPs [19]. Gumiero et al. (2013) investigated effect of TiO2
photocatalytic activity in a HDPE-based food active packaging on the
microbiological stability of a short-ripened cheese. According to their
results, the growth of lactic acid bacteria and coliforms is inhibited by
using this type of packaging [27]. In another study, Chorianopoulos
et al. (2011) showed the significant photocatalytic antibacterial activity
of TiO2 NPs against L. monocytogenes bacterial biofilm disinfection in
food processing [28].
Haghighi et al. (2013) evaluated the antifungal activity of TiO2 NPs
on fungal biofilms standard strains of C. albicans. According to results,
the synthesized TiO2 NPs improved the antifungal effect of C. albicans
biofilms on fluconazole resistant strain. The authors suggested that
TiO2 NPs can effectively inhibit the fungal biofilms particularly those
formed on the surface of instruments [18]. Alizadeh Sani et al. (2017)
investigated the antibacterial effects of bio-nanocomposite films in-
corporated with TiO2 NPs on Gram positive (L. monocytogenes, S.
aureus) and Gram negative (E. coli O157:H7, S. enteritidis and P. fluor-
escens) bacteria in packaged lamb meat samples. They demonstrated
that TiO2 NPs significantly inhibited the growth of test bacteria, espe-
cially on the Gram positive bacteria [29]. Photocatalytic properties of
TiO2 NPs help them eradicate bacteria efficiently. In fact, it must be
indicated that TiO2 NPs produce ROS under UV light. Carre et al.
(2014) mentioned that the antibacterial photocatalytic activity is ac-
companied by lipid peroxidation which increase the membrane fluidity
and disrupt cell integrity [30]. Nevertheless, using TiO2 NPs under UV
light is restricted due to genetic damage in human cells and tissues
[31]. It has been demonstrated that, doping TiO2 NPs with metal ions is
a significant strategy for overcoming this problem. Moreover, anti-
bacterial and photocatalytic properties of TiO2 NPs are significantly
increased by doping them with metal ions Fig. 2 [31,32]. In other
words, doping with metal ions shifts TiO2 NPs light absorption range to
visible light and therefore, there is no need to irradiate them with UV
A. Khezerlou et al.
light (Abamor et al., 2016). Incorporation of TiO2 NPs with nontoxic
polymers is a new another approach to overcome the toxicity problems
of TiO2 NPs.
2.2. Zinc oxide NPs (ZnO)
The safety of ZnO and its compatibility within human skin make it a
proper additive for food application and surfaces that come in contact
with the human body and food products (Ravindranadh et al., 2013;
Hajipour et al., 2012). Indeed, ZnO NPs show antibacterial effects on
Gram-positive and Gram-negative bacteria as well as spores which are
resistant to high temperature and high pressure (Li et al., 2013). The
efficient antibacterial activity of ZnO NPs compared to micro-particles
is related to nanoparticle's surface area enhancement [2,33,34]. Ya-
mamoto et al. (2001) investigated influence of concentration and par-
ticle size on the antibacterial activity of ZnO NPs against S. aureus and
E. coli. Based on his results, it was observed that the antibacterial ac-
tivity of ZnO increased with reducing particle size and increasing
powder concentration [35]. Padmavathy et al. (2008) evaluated the
antibacterial effects of ZnO NPs with various particle sizes. The results
indicated that the bactericidal efficacy of ZnO NPs increases by decline
in particle size [34].
Azam et al. (2012) illustrated the comparative antimicrobial activity
of ZnO, CuO, and Fe2O3 NPs against Gram-negative (E. coli and P.
aeruginosa) and Gram-positive (S. aureus and B. subtilis) bacteria.
According to results, the highest Antibacterial activity was reported for
ZnO NPs while Fe2O3 NPs exhibited the least bactericidal effect [36].
In particular, ZnO decreases bacteria viability; however, the main
and accurate mechanism of its antibacterial activity has not been well
understood. One proposed possibility is the generation of hydrogen
peroxide (H2O2) as the main factor of antibacterial activity. According
to results, another mechanism mentioned for the antibacterial effect of
ZnO NPs is the accumulation of particles on the bacteria surface due to
electrostatic forces [37]. In addition, ROS generation on the surface of
particles, zinc ion release, membrane dysfunction, and NPs inter-
nalization could also be considered as possible reasons for cell damage
[38]. Moreover, in the case of few metal NPs such as Ag and Zn, in-
terruption of transmembrane electron transportation has been stated
[39–41]. Espitia et al. (2013) studied antimicrobial activity ZnO NPs
against foodborne pathogens and spoilage microorganisms. Based on
their results, ZnO NPs had no considerable antimicrobial activity
against P. aeruginosa, L plantarum, and L. monocytogenes. However, it
showed significant antimicrobial activity against E. coli, S. choleraesuis,
S. aureus, Saccharomyces cerevisiae, and A. niger [42]. Xie et al. (2011)
investigated the antibacterial activity of ZnO NPs against C. jejuni. They
suggested that the antibacterial mechanism of ZnO NPs can be attrib-
uted to the disruption of cell membrane and oxidative stress in C. jejuni.
Results showed that ZnO NPs lead to morphological changes and
membrane leakage, and increase oxidative stress gene expression in C.
jejuni [33]. Interestingly, Ag NPs show antibacterial activities even in
ultra-low concentrations [20]; nevertheless, the antibacterial activity of
ZnO NPs is depended on concentration and surface area. Thus ZnO NPs
display better antibacterial activity in higher concentrations and larger
surface area [4]. In another study, Liu et al. (2009) and He et al. (2011)
indicated the effects of changing the concentration of ZnO NPs on the
inhibition of E. coli O157:H7 (bacteria) and Botrytis cinerea and P. ex-
pansum (fungi). The antibacterial activity increase as the concentration
of ZnO NP increased [43,44]. Similarly, Jin et al. (2008) illustrated that
increasing the concentration of ZnO NPs inhibited the growth of
foodborne pathogenic bacteria including; L. monocytogenes, S. En-
teritidis, and E. coli O157:H7 [45]. Hossein-khani et al. (2011) evaluated
the antibacterial effects of ZnO nanoparticle against Shigella dysenteriae.
According to their results, a significant reduce in bacteria count was
observed as a result of particles size reduction [46]. Emami-Karvani
et al. (2011) studied the antimicrobial characteristics of ZnO NPs
against Gram-positive (S. aureus) and Gram-negative (E. coli) bacteria.
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Microbial Pathogenesis 123 (2018) 505–526
They evaluated the antibacterial activity of ZnO NPs according to
concentration and particle size reduction. They indicated that the an-
tibacterial activity of ZnO NPs increases with reducing particle size and
increment concentration; however, ZnO bulk showed no significant
antibacterial activity [47]. Few studies have proven that preparation of
metal ion doped NPs could improve the antimicrobial properties of NPs
[32,48,49]. Akbar et al. (2014) evaluated the antibacterial effects of
ZnO NPs that were prepared using hydrothermal synthesis against S.
typhimurium and S. aureus. They demonstrated that the ZnO NPs loaded
film effectively inhibited the growth of foodborne pathogens bacteria
[50]. Sun et al. (2014) synthesized titanium-doped ZnO powders from
different zinc salts. Results displayed that titanium doped ZnO powders
had antibacterial activity against E. coli and S. aureus. The authors
claimed that the antibacterial properties of titanium-doped ZnO pow-
ders are related to crystallinity and particle size reduction Fig. 2 [48].
Furthermore, ZnO NPs exhibit high photocatalytic characteristics which
improve their antimicrobial properties and produce ROS under UV light
as well [20,51]. An increasing antimicrobial effects of ZnO NPs was
shown by Azam et al. (2012) against the following microorganisms, in
the order of sensitivity: A. niger < C. albicans < P. aeruginosa
(G−) < E. coli (G−) < S. aureus (G+) < B. subtilis (G+) [36]. The
antimicrobial activity of ZnO NPs have been proven against C. albicans.
ZnO was added into edible food linings which were used in packaging
to avoid spoilage and to maintain the color, its mechanical capability,
constancy and food safety [52]. Moreover, ZnO represented antifungal
activity against Pythium spp [53]. Antifungal activities of ZnO NPs and
their mode of action against two postharvest pathogenic fungi (Botrytis
cinerea and P. expansum) were investigated. These results suggest that
ZnO NPs could be used as an effective fungicide in agricultural and food
safety applications [44]. Another study, promising particle size de-
pendent antibacterial and antifungal activities of the ZnO NPs have
been observed [54]. Thessicar et al. (2012) provided new insights into
the anti-HSV-2 effects of ZnO and rationalize their development as a
HSV-2 trapping agent for the prevention and/or treatment of infection.
The observed results also demonstrate that blocking HSV-2 attachment
can have prophylactic as well as therapeutic applications [55].
2.3. Silver NPs (Ag/Ag2O)
According to evidences, Ag NPs are considered as the most common
inorganic NPs used as antimicrobial agents [56]. The antimicrobial
application of Ag additives is widely benefitted in various plastic and
biopolymer products, textiles and coating-based materials [57]. Ag NPs
also possess a wide range of biomedical applications [1]. It has been
revealed that, Ag NPs show high antimicrobial activities compared to
their ionic form [58]. It has also been indicated that Ag NPs are po-
tential antimicrobial agents against wide range bacteria [31]. Ac-
cording to researches, the antibacterial action of Ag NPs is resulted
from damage of the outer membrane bacteria [59]. Many literature
revealed that Ag NPs can induce pits and gaps in the bacterial mem-
brane and eventually fragment the cell [60,61]. Additionally, Ag ions
interact with disulfide or sulfhydryl groups of enzymes that lead to the
disruption of metabolic processes and finally, cell death [57]. Shahverdi
et al. (2007) studied the effect of size reduction on the antimicrobial
properties of Ag NPs. They used Ag NPs to control S. aureus and E. coli
[62]. Jo et al. (2009) tested the efficacy of Ag NPs on different types of
pathogens such as foodborne fungi which rarely produce spore. Ac-
cording to their results, Ag NPs (20–30 nm) penetrate and colonize
better within the plant tissue. They proposed that, Ag NPs were effec-
tive in controlling spore-producing fungal plant pathogens. They also
offered that Ag NPs may be less toxic than synthetic fungicides [58]. In
another study, Mie and et al. (2014) evaluated the antibacterial activity
of synthesized Ag NPs against eight micro-organisms using the disk
diffusion method. The results showed that Ag NPs had potential anti-
bacterial activity against gram-negative bacteria. Thus, the authors
suggested that synthesized Ag NPs could be applied in difference
A. Khezerlou et al.
industries including food, pharmaceutical and biomedical [63]. Choi
et al. (2008) illustrated the inhibitory effects of silver NPs against E. coli
PHL628-gfp [64]. In another study, the comparative was done between
bactericidal activity of Ag, ZnO, and Au NPs on S. mutans. The results
demonstrated that Ag NPs exhibit several effects in controlling S. mu-
tans. Therefore, the authors suggested that Ag NPs can be used in dental
caries since they are commonly caused by S. mutans [65]. Emamifar
et al. (2011) indicated effect of nanocomposite packaging containing Ag
and ZnO on inhibition of L. plantarum in orange juice [66]. Birla et al.
(2009) evaluated the antibacterial effect of Ag NPs against foodborne
bacteria namely E. coli, P. aeruginosa and S. aureus by disc diffusion
method [67]. Zarei et al. (2014) investigated the antibacterial effect of
Ag NPs against four foodborne spoilage and pathogenic bacteria such as
S. typhimurium, L. monocytogenes, V. parahaemolyticus and E. coli. Ac-
cording to the results, Ag NPs had significant antibacterial effects on the
mentioned bacteria. They concluded that Ag NPs can be a suitable al-
ternative for cleaning and disinfecting equipment and surfaces in food-
related environments [68].
Researchers have also been studied the shape-dependent properties
of NPs. Pal et al. (2007) assessed the shape dependent antibacterial
activities of Ag NPs (spherical, rod-shaped and truncated triangular).
The findings showed that, truncated triangular NPs had higher anti-
microbial activity because of their high-atom-density surfaces [11]. In
another study, Bera et al. (2014) evaluated the size and shape-depen-
dent antimicrobial activity of Ag NPs against P. aeruginosa (Gram ne-
gative bacteria) and S. epidermidis and B. megaterium (Gram positive
bacteria). They confirmed that the shape and size of these particles are
controlled by their activity. These results displayed that, the smaller
particles were able to easily penetrate the cell wall and enhance anti-
microbial activity. The authors offered that Ag NPs can be used for
different purposes such as bio adhesives, clinical therapy, biofilms,
coating materials and food packaging [12]. Rajeshkumar et al. (2014)
showed the antibacterial effect of Ag NPs against B. subtilis, K. planti-
cola, K. pneumoniae, S. nematodiphila, and E. coli by disc diffusion
method [69]. Bahrami studied on Ag-Au alloy NPs for evaluating their
antimicrobial properties against S. aureus. The antibacterial activity of
Ag-Au alloy NPs intensified when combined with penicillin G and pi-
peracillin [70]. Ag2O NPs have also been mentioned for their significant
antimicrobial activity [31]. It is believed that, metal oxide NPs may be
considered as a new alternative for most antibacterial agents [31,71].
Sondi and Salopek (2004) illustrated the antimicrobial efficacy of Ag2O
NPs against E. coli. They indicated that when E. coli is exposed to these
NPs, DNA loses its replication ability and the cell cycle is halted at the
G2/M phase resulting in DNA damage. Eventually, the cells are affected
by apoptosis and oxidative stress, occurs [72]. Besides, Ag has been
reported to be less toxic than most disinfectants. Jones and Hoek (2010)
reviewed the antibacterial mechanisms of the Ag NPs and potential
implications in human health and environment [73].
Ag NPs have been used to determine antiviral activity against HIV-1
at non-cytotoxic concentrations [74]. Based on their results, Ag NPs
revealed clear anti-HIV activity at an early stage of viral replication,
and was considered as a virucidal or an inhibitor of viral entry agent.
The author suggested that, it is possible that, Ag NPs prevent fusion,
infectivity and CD4-dependent virion binding, and act as an effective
virucidal agent against both cell-associated virus and cell-free virus.
Furthermore, Ag NPs prevent post-entry stages of the HIV-1 life cycle. It
can be concluded that these characteristics made them a wide-spectrum
antiviral agent that could be used preventively against variety of viral
strains. Pinto et al. (2009) investigated inhibition of Herpes Simplex
Virus Type 1 infection by Ag NPs capped with mercaptoethane sulfo-
nate. Ag NPs compete with virus for binding to cellular heparan sulfate
through their sulfonate end groups. This results led to inhibition of viral
entry into the cell and prevent of subsequent infection [75]. These NPs
have no toxic effects on the host cells. Several other studies have also
reported the antiviral activity of Ag NPs against the hepatitis B virus,
HIV 1, respiratory syncytial virus, and monkey-pox virus [76–79].
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Microbial Pathogenesis 123 (2018) 505–526
Considering all above-mentioned arguments, further research should be
conducted in order to develop Ag compounds and composites with at
least toxicity and maximum antimicrobial activity.
2.4. Copper NPs (Cu/CuO)
Cu NPs due to their unique biological, chemical and physical
properties, antimicrobial activities as well as inexpensiveness are of
great interest to scientists [80–82]. Yoon et al. (2007) examined sus-
ceptibility constants of B. subtilis and E. coli to Ag and Cu NPs. They
proved that reaction of Cu NPs with B. subtilis illustrated the highest
susceptibility whereas the reaction of Ag NPs with E. coli displayed the
lowest one [83]. Usman et al. (2013) evaluated the antimicrobial ac-
tivities of Cu-chitosan NPs. In their studies they assessed the anti-
bacterial and antifungal activities of NPs on several microorganisms,
including B. subtilis, P. aeruginosa, methicillin-resistant S. aureus, S.
choleraesuis, and C. albicans. Additionally, they introduced these NPs as
antimicrobial agents [81]. Nevertheless, Cu NPs act at high con-
centrations as a prooxidant, and rapid oxidation of Cu NPs limit their
application [81,84]. Ren et al. (2009) investigated the antibacterial
properties of CuO NPs against S. aureus EMRSA-16 (epidemic methi-
cillin-resistant S. aureus), EMRSA-15, methicillin-resistant S. aureus
(MRSA) 252, S. aureus ‘Golden’ and S. aureus Oxford (NCTC 6571); S.
epidermidis SE-51 and SE-4; E. coli NCTC 9001; P. aeruginosa PAOI, and
Proteus spp. Results revealed that CuO NPs incorporated into polymers
suggest release of ions might be required for optimum bactericidal [85].
Mahapatra et al. (2008) examined the antibacterial activity of CuO NPs
against S. paratyphi, P. aeruginosa, Klebsiell apneumoniae, and Shigella
strains. According to their results, these NPs showed efficient anti-
bacterial activity against these bacteria. The authors suggested that
crossing NPs through the bacteria cell membrane and then damaging
the vital enzymes of bacteria were the critical factors that triggered cell
death. They also demonstrated that these NPs were not cytotoxic on
HeLa cell line [84]. Bogdanovic et al. (2014) investigated the anti-
microbial activity of Cu small NPs (∼5 nm) with narrow size distribu-
tion against microorganisms of public concern (E. coli, S. aureus and C.
albicans). Based on their results, Cu NPs exhibited significant anti-
microbial activities toward different kinds of microorganisms (E. coli, S.
aureus, and C. albicans) [86]. Azam et al. (2012) showed the size-de-
pendent antibacterial activity of CuO NPs. They evaluated the anti-
bacterial activities of CuO NPs against Gram-positive bacteria (S. aureus
and B. subtilis) and Gram-negative bacteria (P. aeruginosa and E. coli).
Based on their results, CuO NPs exhibited inhibitory effects against both
groups of bacteria. The authors concluded that the bactericidal activity
of CuO NPs depends on their size, stability, and concentration along
with growth medium. The authors also proved that, NPs restrict bac-
terial growth via passing through nanometeric pores present on the
cellular membranes of most bacteria [36,87]. Ahamed et al. (2014)
showed that CuO NPs had significant antimicrobial activity against
various bacterial (E. coli, Shigella flexneri, P. aeruginosa, Klebsiella
pneumonia, S. typhimurium Enterococcus faecalis, Proteus vulgaris, and S.
aureus). Among these pathogens, K. pneumonia exhibited almost re-
sistant to these NPs while E. coli and E. faecalis showed highest sensi-
tivity to CuO NPs [82]. In another study, Ramyadevi et al. (2012) tested
the antimicrobial activity of Cu NPs against S. aureus, Micrococcus lu-
teus, Klebsiella pneumoniae, E. coli, and P. aeruginosa, fungus like A.
flavus, A. niger and C. albicans. The Cu NPs revealed more inhibitory
activity in bacteria compared with the fungus and it also exhibited more
zone of inhibition in E. coli than C. albicans [88].
2.5. Gold NPs (Au)
Au NPs are considered to be valuable in the development of anti-
bacterial agents because of their nontoxicity, polyvalent effects, high
ability to functionalization, ease of detection and photo thermal activ-
ities [89–92]. Although generation of ROS is the main cause of cellular
A. Khezerlou et al.
death for most antibacterial agents and NPs; however, antimicrobial
activity of Au NPs is not induced by ROS-related processes [93].
Giancivincenzo et al. (2010) evaluated Au NPs capped with amphiphilic
sulfate-ended ligands as anti-HIV agents. Their results showed that, the
Au NPs coated with multiple copies of an amphiphilic sulfate-ended
ligand inhibit the HIV infection at nanomolar concentrations in vitro.
Nanoparticle with multiple ligands creates a many local binding mo-
lecules which can help the targeted biological interaction. The authors
suggested that the multivalent Au NPs can be considered as a novel anti
HIV agent for targeting the fusion/adsorption process of the virus in-
fection [13]. Sametband et al. (2011) investigated effective inhibition
of influenza virus by anionic Au NPs. Their results showed that, the
anionic Au NPs have effective inhibition properties against several in-
fluenza strains. The initial mechanism of inhibition Au NPs usually
attributed to the blocking of viral attachment to cell surface. The var-
iation in the degree of inhibition with the anionic groups demonstrated
that the charge density and the functional groups play an important role
in the antiviral activity of the NPs [94]. The small size of the Au NPs
enables them to penetrate into the cell through the endosome vesicle
and possibly interfere with the fusion step as well [95]. Many studies
indicated low or no Au NPs cytotoxicity, and their toxicity if present is
related to the size, shape and nanoparticle's surface charge [96]. The
NPs contain Au core and mercaptoethanesulfonate molecules have
bonded to its surface through the thiol group showed no cytotoxicity
and inhibited various influenza virus strains. Cui et al. (2012) in-
vestigated that the antibacterial activity of Au NPs is attributable to 1)
attachment of these NPs to the bacteria membrane followed by mem-
brane potential modification and ATP level decrease 2) inhibition of
binding tRNA to ribosome [93]. Tiwari et al. (2011) tested the anti-
bacterial and antifungal activities of Au NPs functionalized with 5-
fluorouracil against M. luteus, S. aureus, P. aeruginosa, E. coli, A. fumi-
gatus, and A. niger. The authors reported that these NPs are efficient on
Gram negative bacteria than Gram positive ones because of their easier
internalization into Gram negative bacteria. Additionally, they proved
that these NPs indicate antifungal activity against A. fumigatus and A.
niger [90]. Zawrah et al. (2011) illustrated antimicrobial activities of
drugs (fluconazole and ciprofloxacin) coated with Au NPs. Results
showed that, antimicrobial activities of Au NPs had been increased with
increasing volume. According to results, Best antifungal activity ob-
served on using fluconazole coated with Au NPs against A. niger, C.
albicans and A. flavus. Minimum inhibitory concentration test (MIC)
revealed synergistic effect of Au NPs with ciprofloxacin. Best results
were demonstrated against both Gram negative (S. Typhimurium, E. coli
O157:H7 and P. aeruginosa) and Gram positive (L. monocytogenes, B.
cereus and finally S. aureus) [97]. Zhou et al. (2012) evaluated the
antibacterial activities of Au and Ag NPs against E. coli and B. Calmette-
Guerin (BCG). They asserted that, Au and Ag NPs exhibit significant
antibacterial activity against both Gram negative (E. coli) and Gram
positive bacteria (BCG). They also functionalized Au NPs with strong
bound capping (poly-allylamine hydrochloride) and weak bound cap-
ping agents (citrate). Poly-allylamine hydrochloride is able to directly
contact with bacteria cell membrane because of its positively charged
nature [91]. In addition, Au NPs functionalized by strong bound cap-
ping agents can self-assemble into 4–5 μm long chains [98]. Zhou et al.
(2012) explained that the two mentioned processes facilitate the de-
livery of a large number of Au NPs on the bacteria cell wall. In contrast,
extra-accumulation of weak bound capping agents such as citrate de-
crease surface area and reduce interactions with NPs. Accordingly, Au
nanoparticle with the same shape and size but different capping agent
display different antimicrobial activities [73]. Jayaseelan et al. (2013)
proved antifungal activity of green synthesized of Au NPs using seed
aqueous extract of Abelmoschus esculentus against Puccinia graminis tritci,
A. flavus, A. niger and C. albicans using standard well diffusion method.
The authors suggested that the synthesized Au NPs can be act as an
effective antifungal agent [99]. In another study, Lima et al. in-
vestigated the antimicrobial effect of Au NPs against S. typhi and E. coli
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Microbial Pathogenesis 123 (2018) 505–526
bacteria. Based on their results, these NPs decreased about 90–95% of S.
typhi and E. coli colonies. The authors stated that, the main factors that
influenced the bactericidal properties were roughness and dispersion of
Au NPs on the medium [89]. It seems that Au NPs are safer on mam-
malian cells than other NPs because of ROS-independent mechanisms.
Furthermore, the high ability of these NPs for functionalizing make
them ideal nanomaterials for applying as targeted antimicrobial agents.
2.6. Silica NPs (SiO2)
The antimicrobial activity of SiO2 is more significant at nano-scale
due to surface area enhancement [100]. Cousins et al. (2007) revealed
that Si NPs inhibit bacteria adherence to oral biofilms [101]. The
combination usage of Si NPs with other biocidal NPs such as Ag have
been extensively investigated in the recent years. Kim et al. (2006) were
examined the antibacterial properties of the Cu/SiO2 nanocomposite by
disk diffusion methods. For antibacterial test, S. aureus, E. coli, E.
cloacae, C. albicans, and P. citrinum were selected as indicators. Results
demonstrated that the antibacterial activities of Cu-SiO2 nanocomposite
were clearly detected against Gram-negative, Gram positive bacteria,
and fungi due to Cu NPs of Cu-SiO2 nanocomposite were well formed on
the surface of SiO2 nanoparticle without aggregation of the Cu NPs and
had large surface area [102]. Similarly, Kim et al. (2007) were eval-
uated the antibacterial properties of the Ag/SiO2 nanocomposite by
disk diffusion methods against S. aureus, P. aeruginosa, E. coli, E. cloacae,
C. albicans, A. niger and P. citrinum And achieved similar results [103].
Egger et al. (2009) assessed the antimicrobial activity of novel Ag-Si
nanocomposite. Their results revealed better antimicrobial function of
nanocomposite against a wide range of microorganisms compared to
conventional materials, such as silver nitrate and silver zeolite [57]. In
another study, Mukha et al. investigated synthesized Ag/SiO2 and Au/
SiO2 nanostructures and their antimicrobial activity. Results indicated
that Ag/SiO2 nanocomposites improved antimicrobial properties
against E. coli, S. aurous, and C. albicans while Au/SiO2 nanocomposites
did not show any antibacterial activity against the tested microorgan-
isms. The authors claimed that these nanocomposites could be used for
water disinfection and food and pharmaceutical application [104]. In
another study, Xu et al. (2009) were tested the antibacterial effects of
Ag-SiO2 core-shell particles against E. coli and S. aureus by the usual
serial dilution method for determine minimal inhibitory concentration
(MIC) and minimal bactericidal concentration (MBC). According to
results, the NPs showed considerable antibacterial effects [105]. Sev-
eral studies showed that Si nanowires could interface with living cells
and bacteria interrupting cell functions such as cell differentiation,
adhesion and spreading. Li et al. (2004) revealed the antibacterial ef-
fects of Ag NPs Si nanowires. Their results indicated high antibacterial
activity for these nanostructures. They also showed that, these nanos-
tructures are biocompatible with human cell namely lung adenocarci-
noma epithelial cell [9,106]. Fellahi et al. (2013) assessed the anti-
bacterial activity of Si nanowire substrates decorated with Ag or Cu
NPs. According to author's results, the NPs revealed strong antibacterial
activity against E. coli. Ag decorated with Si nanowires was found to be
biocompatible with human cell while Cu decorated with Si nanowires
show high cytotoxicity [10]. All of these studies signify that the de-
velopment of Si compounds and composites especially their nano-
composites together with NPs such as Ag show good potential on the
development of antimicrobial agents. In addition, the non-toxicity
properties of Si NPs introduce them as antimicrobial agents in food and
biomedical applications.
2.7. Magnesium oxide NPs (MgO) and calcium oxide NPs (CaO)
Due to the alkalinity and active oxygen species of CaO and MgO,
they provide strong antibacterial activity. It has been proved that the
antibacterial mechanism of CaO and MgO NPs attributed to the gen-
eration of superoxide on the surface of these particles, and also increase
A. Khezerlou et al. Microbial Pathogenesis 123 (2018) 505–526

Fig. 4. Schematic comparison of NPs-induced general toxicity via active internalization mechanisms, and endocytosis-free NPs.
“NPs enter cells by energy-dependent processes, and rapidly confine in vesicular structures, endosomes, and lysosomes. Acidic lysosomal pH, triggers a lysosome-
enhanced Trojan horse effect (LETH effect) that combines the abundant cellular internalization of the NPs via active processes which consequently enhances the
release of relatively toxic ions (e.g., Ag, Au ions). Significant amounts of intracellularly leaked ions may then exert ion-specific toxicity (e.g., enzyme depletion/
inactivation, protein denaturation, etc.) against particular cellular targets (e.g., mitochondria, RER) and/or lysosomal damage/dysfunction. Finally, it results in ROS
level increase, apoptosis, DNA and membrane damage”.

in pH value via the hydration of CaO and MgO [107]. According to
results, MgO NPs damage the cell membrane and then cause the leakage
of intracellular contents which in turn lead to bacterial cell death [108].
Hewitt et al. (2001) indicated that MgO initiates the sensitivity changes
of E. coli induced by active oxygen [109]. Nevertheless, Leung et al.
(2014) described that strong antibacterial activity of MgO NPs can be
observed in the absence of ROS production. They declared that the
mechanism of antimicrobial activity may be due to cell membrane
damage [110]. In fact, MgO NPs initiate bactericidal activity against
both Gram-positive and Gram negative bacteria [111]. Sawai et al.
(2000) evaluated the antibacterial activity of MgO against E. coli and S.
aureus. They stated that the presence of active oxygen, such as super-
oxide, on the surface of MgO NPs is one of the main factors that affects
antibacterial activity [112]. Jin et al. (2011) also investigated the an-
tibacterial activities of MgO NPs alone or in combination with other
antimicrobials (nisin and ZnO NPs) against E. coli and S. Stanley. MgO
NPs demonstrated strong bactericidal activity against these pathogens
According to their results, the antibacterial activity of MgO NPs im-
proved as MgO concentrations increased. The authors showed that MgO
NPs alone or in combination with niacin could be used as an effective
antibacterial agent for enhancing food safety [108]. Yamamoto et al.
(2010) examined the antimicrobial efficiency of CaCO3 NPs. According
to results, CaCO3 was converted to CaO due to heat treatment. CaO NPs
displayed bactericidal activity against E. coli, S. typhimurium, S. aureus
and B. subtilis [107]. Yamamoto et al. (2010) evaluated the anti-
bacterial activity of CaCO3/MgO nanocomposites against Gram-
negative (E. coli) and Gram-positive (S. aureus) bacteria. Results ex-
hibited more antibacterial action against S. aureus compared to E. coli.
Based on the authors results, the antibacterial effect of CaO and MgO
was because of the generation of superoxide on their surface and also
increase in pH value due to CaO and MgO hydration [107].
Vidic et al. (2013) investigated the antimicrobial activity of mixed
nanostructures of ZnO-MgO. They also compared the antimicrobial
activity of ZnO-MgO NPs with pure ZnO and MgO NPs. Based on their
findings, ZnO nanocrystals illustrated high antimicrobial activity
against both Gram-negative (E. coli) and Gram-positive (B. subtilis)
bacteria. MgO NPs exhibited moderate activity and ZnO-MgO NPs re-
vealed high antibacterial activity against Gram-positive bacteria.
Microscopic analysis displayed that B. subtilis cells were damaged after
contact with ZnO-MgO NPs. They suggested that nanostructured ZnO-
MgO can be used as a safe and new therapeutic agent for overcome
bacterial [111]. Results indicate that, MgO and CaO NPs alone or in
combination with other antibacterial agents show great antibacterial
activities. These NPs also are inexpensive, available materials and
biocompatible. Thus they are considered as promising antibacterial
agents [110]. Researchers suggest that, these materials can be utilized
in environmental preservation as well as in medical treatments and
food processing [113].
2.8. Aluminum oxide NPs (Al2O3)
Aluminum oxide NPs is used for different applications in industrial

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Fig. 5. Molecular mechanisms of ROS-mediated cell death pathway.

“TiO2 NPs and ZnO NPs induce ROS-mediated cell apoptosis, autophagy or necrosis. The increase of ROS level in cytoplasm results in thioredoxin (Trx) oxidation and
apoptosis signal-regulating kinase 1 (ASK1) activation. ASK1 phosphorylate mitogen-activated protein kinases (ERKs, JNKs, and p38 MAPKs) that control the AP-1-
mediated synthesis of pro- (Bak, Bax) and anti-apoptotic (Bcl-2, Bcl-xL) proteins, as well as death ligands (FasL), and eventually promote cell apoptosis. Likewise,
ERKs promote cell apoptosis trough attenuation of AKT kinase activity that controls NF-κB-mediated synthesis of Bcl-2 and Bcl-xL proteins. The oxidative damages of
the mitochondria results in the dissipation of mitochondrial membrane potential (ΔΨm), decrease of ATP level and release of cytochrome c (Cyt. c) to the cytosol. Cyt.
c, bind to apoptotic protease activating factor 1 (Apaf-1) and induce caspase-dependent apoptosis. The increase of ROS level in nucleus results in the activation of
ataxia telangiectasia mutated (ATM), as well as ataxia telangiectasia and Rad 3-related (ATR) kinases which induces p53-mediated apoptosis and increase DNA
double-strand breaks marker (γH2AX) level. ROS-induced endoplasmic reticulum stress results in JNK1-mediated increase of pro-autophagic protein (Beclin-1) level
and AMPK-mediated suppression of autophagic inhibitors and the rapamycin (mTOR) kinase. Both processes lead to cell autophagy. Oxidative injury of the plasma
membrane results in the downregulation of the plasma membrane calcium ATPase 1 (PMCA1), and decrease ATP level and increase Ca2+ level” [333].

and personal care products. The antimicrobial effects of aluminum NPs
have been evaluated on E. coli [114]. Aluminum NPs exhibited a
moderate growth-inhibitory effects against tested bacteria, only at very
high concentrations. The antimicrobial effects of aluminum NPs are
usually attributed to surface charge interactions between the NPs and
cells membrane and wall and also penetration inside the bacterial cells.
However, it is believed that the free-radical scavenging properties of the
NPs might have prevented intense antimicrobial action and cell wall
disruption [114].
Aluminum NPs has a corundum-like structure. It is thermo-
dynamically stable over a wide range of temperature [115]. The Al NPs
at close-neutral pH carry a positive charge on its surface. The electro-
static interaction between the negatively charged microorganisms
namely E. coli cells and the NPs leads to the adhesion of Al NPs on the
bacterial surfaces [116]. Increasing the concentration of NPs in the
suspension increased the reaction and adhesion levels. The
phenomenon of bacterial cell adhesion onto the NPs usually attributed
to the electrostatic interaction between bacteria cell and nanoparticle
surface, along with hydrophobic interactions and polymer cross-link.
The antimicrobial properties of NPs are related to the generation of
reactive oxygen species (ROS) which leads to disruption of cell wall and
membrane and subsequently cell death [117]. Versus, Al NPs may act as
free radical scavengers. NPs can rescue cells from oxidative stress-in-
duced cell death so that appears to be dependent on the structure of the
nanoparticle and independent of its size [118]. Ansari et al. (2013)
investigated the antibacterial activity of Al NPs against methicillin-re-
sistant coagulase negative S. aureus by serial dilution method and de-
termination of MIC. They presented that a novel Al NPs are effective
bactericidal agents regardless of the drug resistance mechanisms that is
important to these bacteria as a pathogen [119]. Recently, the anti-
microbial activity of Al NPs to microalgae has been examined by Sadiq
et al. (2011) [120]. They evaluated micron and nano sized Al NPs

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Table 1
NPs as antimicrobial agent, properties and their mechanisms of action.
NPs (NPs) The main factors for The proposed antimicrobial mechanism for NPs Important properties as antimicrobial agent Reference
antimicrobial activity

TiO2 NPs Crystal structure, shape No toxicity in dark condition; Oxidative stress via the Suitable photocatalytic properties; high stability; effective [170]
and size. generation of ROS; lipid peroxidation that lead to enhance antifungal for fluconazole resistant strains. [171]
membrane fluidity and disrupt the cell; Toxic only under UV [172]
illumination and killed approximately all bacteria. [173]
Photoactivation of TiO2 promotes bactericidal effect [174]
peroxidation of the polyunsaturated phospholipid of [175]
membrane; loss of respiratory activity [176]

ZnO NPs Particle size and ROS generation on the surface of the particles; zinc ion Photocatalytic activity; high stability; bactericidal effects on [177]
concentration. release; membrane dysfunction and NPs internalization into both Gram-positive and Gram-negative bacteria; antibacterial [178]
cell; Electrostatic interaction, morphological changes in the activity against spores which are resistant to high [179]
presence of ZnO NPs, increase in membrane permeability temperature and high pressure. [180]
and NPs accumulation in the cytoplasm
Ag NPs Particle size, Induction of pits and cavity in the bacterial cell membrane; High antimicrobial activity against both bacteria and drug- [181]
concentration and shape interact with disulfide or sulfhydryl groups of enzymes and resistant bacteria, antifungal activity on spore- producing [182]
of particles. disruption of metabolic processes. Ion release; DNA loses its fungal plant pathogens, high stability, nontoxicity [65]
replication ability and the cell cycle halts at the G2/M phase
owing to the DNA damage (in the case of Ag2O). Disturbs
permeability, respiration, and cell division, interacts with
cell membrane and sulfur- and phosphorus- containing
compounds, Ag NPs-ampicillin leads to cell wall lysis,
penetration of Ag NPs, and prevents DNA unwinding
CuO NPs Particle size and Crossing of NPs from the bacteria cell membrane and then Effective against gram positive and gram-negative bacteria; [85]
concentration. damaging the vital enzymes of bacteria. high stability; antifungal activity. killing bacteria [183]
Au NPs Roughness and particle Attachment of these NPs to membrane which change the Nontoxicity, not inducing any ROS-related process; high [184]
size. membrane potential and then cause the decrease the ATP ability to functionalization, polyvalent effects; ease of [185]
level; and inhibition of tRNA binding to the ribosome detection; photothermal activity.
SiO2 NPs Particle size and shape. Influencing the cell functions such as cell differentiation, Non-toxicity; stability. [102]
adhesion and spreading. [186]
MgO/CaO Particle size, pH and Damaging the cell membrane and then causing the leakage Effective against both grampositive and gram-negative [187]
NPs concentration. of intracellular contents and death of the bacterial cells. bacteria; high stability; low cost; availability. [111]
[188]
Al2O3 NPs Particle size and bacterial attachment (electrostatic interaction); Damage to Toxicity of NPs is from their higher tendency to attach to the [189]
concentration. the bacterial cell wall and increase the permeability cell walls [190]
[191]
[192]
Clay NPs Shape and concentration Electrostatic interaction, adsorption, and penetration of NPs The most effective against gram positive [136]
of particles. and toxicity [193]
[194]

against Scenedesmus sp. and Chlorella sp. According to their results, Al According to their results, nano-hybrids of Ag/clay NPs significantly
NPs exhibited a growth inhibitory effect against both the species and a inhibited the growth of pathogenic bacteria tested including methi-
considerable reduce in the chlorophyll content was also observed in the cillin-resistant S. aureus and E. coli, and Ag/clay NPs showed a stronger
cells treated with NPs. The authors were suggested that an interaction biocidal effect than Ag NPs. Antimicrobial effects are usually attributed
of the NPs with the cell surface can be as the possible mechanism for the to encapsulated bacteria and triggers death signals from the cell
toxicity Al NPs against microalgae's. membrane. These observations suggest that the high electrostatic affi-
nity of clay NPs onto the bacterial surface and facilitate Ag/clay NPs-
cell interaction, causing local membrane damage, finally, cell death
2.9. Clay NPs
[132]. Paulraj Kanmani et al. (2014) evaluated the antimicrobial
properties active nanocomposite films containing gelatin, Ag NPs and
Clay NPs known as layered mineral silicates. These NPs are orga-
nanoclay against E. coli and L. monocytogenes pathogenic bacteria using
nized into several classes such as montmorillonite, halloysite, kaolinite,
agar well diffusion and colony count methods. Based on their results,
bentonite and hectorite, depending on chemical composition and na-
the Ag NPs showed high antimicrobial activity against both bacteria,
noparticle morphology [121–124]. A new group of clay NPs called
but the clay NPs illustrated antimicrobial activity only against to Gram
Organically-modified nanoclays. Organoclays are an attractive class of
positive (L. monocytogenes) bacteria [133]. This property is usually re-
hybrid organic-inorganic NPs that are used for various purposes in
lated to the strong antimicrobial activity of alkyl quaternary ammo-
polymer nanocomposites such as rheological modifiers, gas absorbents,
nium salt group in the organoclay NPs [134]. Gram-positive bacteria
antimicrobial agent and drug delivery carriers [124–128]. Plate-like
have complex structure which is composed of a three-dimensional thick
montmorillonite (MMT) is the most common nanoclay used in nano-
peptidoglycan layer consisting of linear polysaccharide chains cross
materials applications. Montmorillonite depending on surface mod-
linked by peptides, which makes it difficult for Ag NPs to penetrate onto
ification of the clay layers, could be dispersed in a polymer matrix to
Gram-positive bacteria cell [135]. In contrast, Gram-negative bacteria
form nanocomposite [129,130].
are coated by thin peptidoglycan layer and negatively charged outer
Costa et al. (2011) investigated the antimicrobial activity of Ag/
membrane which facilitates the easy penetration of the nanoparticle
MMT NPs to increasing the shelf life of fresh fruit salad. Results showed
into the surface and inside the cell [135]. Bagchi et al. (2013) examined
that Ag/MMT NPs inhibited the growth of spoilage microorganisms
the antibacterial activity of Cu NPs loaded natural MMT clay based on
(mesophilic and psychrotrophic bacteria, coliforms, lactic acid bacteria,
contact inhibition and ion release. The authors reported that, significant
yeasts and molds) [131]. Su et al. (2011) synthesized a new nano-hy-
antimicrobial activity was observed on E. coli, S. aureus, P. aeruginosa
brids of Ag NPs on Clay platelets for inhibiting Ag-resistant bacteria.

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Table 2
Classification antimicrobial activity of NPs.
Properties of NPs Mechanism of action NPs Target microorganism Reference

Antibacterial Interaction with cell membrane and phosphorus moieties in DNA, resulting in Ag NPs E. coli, [195]
inactivation of DNA replication. Generation of ROS, Reacts with sulfur-containing B. subtilis, [196]
proteins, leading to the inhibition of enzyme functions S. aureus, [197]
Methicillin-resistant coagulase-negative [198]
Staphylococci, [199]
Vancomycin-resistant Enterococcus faecium, [72]
ESBL-positive K. pneumonia, [200]
S. typhi, [201]
Vibrio cholera
Au NPs Methicillin-resistant S. aureus, [202]
Vancomycin-resistant Enterococcus faecium, [203]
E. coli, [204]
P. aeruginosa [205]
[184]
TiO2 NPs E. coli 0157:H7, [206]
S. aureus, [207]
L. monocytogenes [174]
S. enteritidis [172]
P. fluorescens, [208]
[209]
ZnO NPs E. coli 0157:H7, [189]
B. subtilis, [43]
P. fluorescens, [45]
L. monocytogenes, [210]
S. enteritidis, [211]
S. aureus,
S. typhimurium
CuO NPs B. subtilis [85]
L. monocytogenes [212]
S. aureus [117]
E. coli
MgO NPs B. subtilis, [213]
E. coli [214]
S. aureus [188]
B. megaterium [110]
CaO NPs S. aureus [215]
S. epidermidis [216]
E. coli [217]
S. mutans
Al2O3 NPs E. coli [116]
P. aeruginosa, [218]
S. aureus [219]
B. subtilis
K. aerogenes
P. desmolyticum
SiO2 NPs E. coli [220]
S. mutans [221]
B. subtilis
Clay NPs E. coli [136]
Enterococcus faecalis [222]
S. aureus,
P. aeruginosa
(continued on next page)

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Table 2 (continued)

Properties of NPs Mechanism of action NPs Target microorganism Reference

Antifungal Disruption of cell membrane Ag NPs C. spp. [223]

Trichophyton. mentagrophytes [224]
Bipolaris sorokiniana [58]
Magnaporthe grisea
ZnO NPs Botrytis cinerea [44]
P. expansum [225]
A. flavus [226]
A. niger [227]
Saccharomyces cerevisiae [228]
C. albicans [227]
Rhizopus stolonifera
Fusarium oxysporum
TiO2 NPs C. spp. [229]
P. expansum [230]
A. niger spp. [231]
P. oxalicum [232]
CuO NPs A. niger, [233]
Rhizopus oryzae, [234]
A. flavus,
Cladosporium carrionii,
Mucor,
S. cerevisiae
P. notatum
Alternaria alternata
MgO NPs Saccharomyces cerevisiae [227]
C. albicans [235]
A. niger
Rhizopus stolonifer
CaO NPs Saccharomyces cerevisiae [227]
C. albicans [235]
A. niger
Rhizopus stolonifer
Au NPs Puccinia graminis tritci, [99]
A. flavus,
A. niger
C. albicans
SiO2 NPs C. spp. [236]
A. spp. [237]
Dermatophytes spp.
Al2O3 NPs C. spp. [238]
Scenedesmus quadricauda [239]
A. niger
Clay NPs Pycnoporus cinnabarinus [240]
Pleurotus ostreatus [241]
A. niger
C. albicans
Antiviral Blocking of viral attachment to cell surface Au NPs HIV virus, [13]
Influenza virus [74]
[242]
Ag NPs HIV-1, [75]
Influenza virus, [74]
Herpes Simplex virus, [76]
Respiratory syncytial virus, [77]
Monkey pox virus [78]
[79]
ZnO NPs Herpes simplex virus type-1 & 2, [55]
Transmissible gastroenteritis virus (TGEV) [243]
[244]
[245]
[246]
TiO2 NPs Inactivates bacteriophages, [247]
Viruses HSV-1 (Herpes simplex virus), [248]
Influenza virus, [249]
Inactivation of Qβ and T4 bacteriophages, [250]
Zika Virus Mosquito Vectors [251]
[252]
[253]
[254]
[255]
(continued on next page)

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Table 2 (continued)

Properties of NPs Mechanism of action NPs Target microorganism Reference

Antiparasite Inhibition of promastigotes proliferation and metabolic activity, Ionic NPs released, TiO2 NPs Leishmania tropica [256]
Inactivation oocysts, Interaction of NPs with the surface of parasites, NPs impair the Leishmania infantum [31]
structure of lipophosphoglycan and glycoprotein molecules that are found on the Leishmania major [257]
surface of parasites and which are responsible for the infection and disturb DNA. Rhipicephalus (Boophilus) microplus [258]
Generated ROS form NPs and inhibition of parasite infection with oxidative stress, Haemaphysalis bispinosa [259]
coordination effects, and non-homeostasis effects. NPs can diffuse into the cell Anopheles stephensi, [260]
directly through the pores present in cell membrane due to their small size, or they Aedes aegypti [261]
get entry through ion channels and transporter proteins present on the plasma Culex quinquefasciatus [262]
membrane. NPs may enter into cells via endocytosis. Leishmania donovani [263]
Ag NPs Leishmania tropica [264]
Leishmania infantum [265]
Entamoeba histolytica [266]
Cryptosporidium parvum [267]
Giardia lamblia, [268]
Fasciola [269]
Plasmodium, [270]
Toxoplasma gondii [271]
Leishmania major [272]
Plasmodium falciparum (malaria parasite) [273]
larvae of malaria vector, [274]
Anopheles subpictus Grassi, filariasis vector Culex [275]
quinquefasciatus Say (Diptera: Culicidae), [276]
Rhipicephalus (Boophilus) microplus Canestrini [277]
(Acari: Ixodidae) [278]
Haemaphysalis bispinosa [279]
Hippobosca maculata [280]
CuO NPs Entamoeba histolytica [268]
Cryptosporidium parvum [281]
Plasmodium [282]
Hematophagous
Au NPs Giardia lamblia, [283]
Plasmodium, [284]
Toxoplasma, [285]
Leishmania donovani [286]
Leishmania major [287]
Cryptosporidium parvum [267]
Hydatid cyst protoscolices of Echinococcus [288]
granulosus [289]
ZnO NPs Leishmania major, [282]
Plasmodium [290]
[266]
MgO NPs Leishmania major [291]
[292]
Chitosan Giardia lamblia [270]
Curcumin Leishmania [293]
Selenium Leishmania donovani [294]
Toxoplasma gondii [295]
Plasmodium [296]
Echinococcus multilocularis albendazole [297]
Trichinella spiralis [298]
[299]

and Enterococcus faecalis. Cellular membrane damage by direct attach-
ment of the NPs and indirect damage caused by released Cu ion are the
main reasons of antibacterial action. NPs did not show any adverse
effects and cytotoxicity on the two human cell lines beyond the M.B.C.
value for the microorganisms tested [136]. Das et al. (2014) reported
that Cu nanoparticle-decorated organically modified montmorillonite/
epoxy nanocomposites significantly inhibited the growth of Gram ne-
gative (Klebsiella pneumonia) and Gram positive (S. aureus) bacteria
[137].
3. The role of NPs versus ions release on antimicrobial activities
Stress and environmental factors affect organisms' susceptibility to
antibiotics by antibiotic-resistant organisms which increase in the ab-
sence of antibiotic reactions [138],environmental adaptation and pro-
tective cellular responses [139,140]. One of the most important causes
of environmental stress is metal cations (namely Cu and Zn) of bacterial
cell activity at low concentrations [141,142], since high concentrations
lead to selective pressure and resistance to antibiotics. Antibiotics
chelate to metal cations such as Cu-penicillin [143], Zn-b-lactam
[144,145], Cu-aminoglycosides [146,147] and Zn-tetracycline [148]
and increase or decrease antibiotic activity [149–151]. The interaction
between antibiotic and metal cations reduce the activity of antibiotics
and/or limits the bioavailability of metal cations against micro-
organism, this procedure may also change membrane penetration and
displays antimicrobial activities [152,153]. Metal cations have synergic
effect against few microorganisms. The synergistic effects of NPs cation
is related to carbapenems, fluoroquinolones, ceftazidime and to-
bramycin against P. aeruginosa, Acinetobacter baumannii and Gram-ne-
gative pathogens [154,155]. However, regarding NPs, the impact is
related to antimicrobial peptides and Gram-positive and Gram-negative
bacteria particularly P. aeruginosa [156,157]. Recently scientist have
discovered Cu-dependent antibiotics, which have Cu-dependent activity
and are deactivate in Cu deficiency [158–160]. Recently antibiotic re-
sistance microorganisms have become of serious concern in public
health [161,162]. Metal oxide NPs systems have shown considerable
antimicrobial activities based on molecular surface. Metal oxide NPs
with porous structure and active center act as novel solutions against

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Table 3
Effects of NPs against various parasites.
NPs Parasites Findings Type of study Reference

Ag NPs Fasciola The percent of non-hatching eggs treated with the Triclabendazole drug was ∼70%, while this percent increased to ∼90% In vivo/In [271]
in combination with drug and Ag NPs. vitro
Ag/chitosan/curcumin NPs Giardia lamblia The most fighter effects obtained by combining the three nanomaterial. The parasite found to be eradicated from intestine In vivo [270]
and stool.
Chitosan NPs Trichinella spiralis Despite stimulation lymphocyte response by chitosan, but the effects of treatment was not protective In vitro [300]
Ag NPs Leishmania tropica Ag NPs indicated significant anti-leishmanial activities by inhibiting the proliferation and metabolic activity of In vitro [265]
promastigotes.
Albendazole/chitosan NPs Echinococcus multilocularis Metacestode grown was greatly suppressed during treatment with nanomaterials. In vivo [301]
Chitosan NPs Leishmania infantum Chitosan NPs did not show significant antileishmanial activity against Leishmania infantum. In vitro [302]
CuO nano-hybrid solids Plasmodium falsiparum The NPs showed significant antimalarial activities against the parasites tested. In vitro [303]
Nano-Nitazoxanide Cryptosporidium parvum Nano nitazoxanide was efficiency on parasites during the study (6th). In vivo [304]

517
Au NPs Leishmania major Simultaneous use of Au NPs and MW irradiation was more deadly for promastigotes and amastigotes compared with MW In vitro [288]
alone.
Ag NPs Leishmania major The combined using of direct current electricity and Ag NPs had a cosiderable synergistic effect on promastigote mortality. In vitro [305]
CuO/Ag NPs E. histolytica, C. parvum The combined using CuO NPs and Ag NPs illustrated a remarkable effect in overcoming cryptosporidiosis and amoebiasis. In vitro [268]
Ag/Chitosan NPs Toxoplasma gondii Using Ag NPs singly or combined with chitosan demonstrated promising anti-toxoplasma potentials. In vivo [306]
Ag/Selenium NPs Leishmania major Ag NPs indicated anti-Leishmanial effects but selenium did not have any significant effect In vivo [307]
Chitosan/tripolyphosphate conjugated chloroquine Plasmodium berghei The highest effects of nanoconjugated chloroquine (Nch) observed at 250 mg/kg Bw concentration during the course of In vivo [308]
NPs treatment (∼15th)
Ag NPs Leishmania tropica The IC50 obtained for Ag NPs solutions in high values (∼15 pg/ml). In vitro [309]
Au NPs Giardia lamblia Au NPs at a concentration of ∼0.3 mg/ml was effective for killing Giardia. In vitro [285]
TiO2/Ag2O NPs Leishmania TiO2 and Ag2O NPs displayed significant antiparasite effects. In vitro [31]
Ag NPs Leishmania major Ag NPs alone had no important lethal effects on Leishmania major Promastigotes. In vitro [305]
Curcumin-loaded lipid NPs Plasmodium berghei Antimalarial activity of curcumin increased with entrapping in lipid NPs against malaria. In vivo [310]
Ag NPs Plasmodium falciparum The Ag NPs indicated considerable antiplasmodial activity against P. falciparum. In vitro [311]
Microbial Pathogenesis 123 (2018) 505–526
 A. Khezerlou et al.

Table 4
A summary of the in vitro and in vivo toxicity studies NPs.
NPs Assays Doses Cell/tissue or Animal Methods Findings References

TiO2 In vitro 20–100 μg/ml Human lymphocytes Cell viability tested by MTT and trypan blue exclusion assays; ROS levels measured Apoptosis induced by p38/JNK and caspase-8- [327]
using H2 DCFDA; TiO2 measured using AAS; Apoptosis tested by Caspase-8 activity dependent bid pathways; Size- and shape dependent
assay; expression levels of phosphorylated stress-responsive p38 and JNK/SAPK oxidative stress
analyzed by Western blotting
TiO2 In vivo 500 μg per mice Mice Intranasal instillation; TiO2 contents determined in the sub-brain regions by ICP-MS; Rutile had lower adverse effects on the CNS than did [334]
pathological changes observed by optical microscopy and TEM anatase
CuO In vitro 0.01–100 μM Human neuroglioma (H4) Cell viability assay using Hoechst and ethidium homodimer-1 dye Dose-dependent toxicity induced [335]
cells
CuO In vivo 50,000–200,000 μg/kg bw Rats Analyzed serum with automatic analyzer; used optical light microscopy for evaluating Hepato- and nephrotoxicity [336]
histopathology; urine, serum and organs analyzed by NMR spectroscopy
ZnO In vitro 0.001–5 μg/ml Human epidermal cell line Cell viability assayed by MTT and neutral red uptake method; DNA damage assessed Genotoxicity and oxidative stress induced [337]
(A431) using comet assay; oxidative stress assayed using markers (GSH level, catalase
activity, SOD activity)
ZnO In vivo 5 μg/kg bw Mice Gastrointestinal administration; serum assayed by automatic biochemical analyzer; Toxic; severe renal damage occurs in the nanoscale [338]
blood element and blood coagulation tested using automatic hematology analyzer ZnO-treated mice

518
and ELISA; histopathology utilized light microscopy
Ag In vitro 0.7 μg/ml Human hepatoma (HepG2) Evaluated toxicity by MTT, Alamar blue, and LDH assays; monitored oxidative stress Oxidative stress mediated toxicity [313]
cells using DCFH-DA; evaluated expression of metal responsive metallothionein by RT-PCR
Ag In vivo 49–515 μg/m3 Rat Exposed whole body in inhalation chamber; observed mortality, body weight, food Higher dose induces inflammatory response; lungs and [339]
consumption; tested pulmonary function; organs histopathologically examined liver major target tissues
Au In vitro 0.2–2 nM Human cell line, HeLa MTT assay performed; TEM analysis performed for internalization study; gene Nontoxic [340]
expression in stress-related genes analyzed
Au In vivo 0.750 μg/ml Mytilus edulis Determined toxicity by measuring protein ubiquitination and carbonylation; Oxidative stress induced [341]
measured catalase activity, lysosomal membrane stability; gill proteins analyzed by
2D gel electrophoresis
Al In vitro 10–100 μg/ml Type II lung epithelium cell LDH, WST-1, and XTT assayed cytotoxicity; intracellular NP accumulation and Cytotoxic [342]
line (A549) distribution studied using TEM
Al In vivo 0–250 μg/ml Daphnia magna Toxicity evaluated by the Microtox test Toxic [343]
Co In vitro 0.1–0.2 μM Human peripheral blood Assayed Co uptake; cytokinesis-block micronucleus assay; DNA damage detected by Internalized by human leukocytes; Genotoxic [344]
leukocytes (PBLs) Comet assay
Co In vitro 0–5 μg/ml Human U937 monocytes Evaluated cell viability using Celltiter 96® aqueous nonradioactive cell proliferation Toxic; act by increasing the transcription and activities [345]
assay; determined ROS using H2 DCF-DA; analyzed expression and secretion of MMP- of MMP-2 and MMP-9
2 and MMP-9 and their specific tissue inhibitors by RT-PCR
SiO2 In vitro 4–400 μg/cm2 Laryngeal epithelial cells Tested cell viability using alamar blue assay; measured cellular ROS by H 2 DCFDA; Nontoxic, induced reversible ROS generation [346]
Human (hep-2 cells) analyzed SOD, catalase, GR and GPx enzymes activity; detected LPO by competitive
ELISA
Microbial Pathogenesis 123 (2018) 505–526
A. Khezerlou et al.
antibiotic resistant microorganisms. The most important factors in an-
timicrobial activity are: chemical properties, particle size, shape and
zeta potential energetic in ROS [163,164]. According to mentioned
studies results, the authors suggested that the main mechanism of an-
timicrobial activity of clay NPs is disruption of bacterial membrane
integrity by ROS generation, similar to others NPs, and clay shows good
effects for use in therapeutic, pharmaceutical and food applications.
Metal oxide in nano scale demonstrate antibacterial activity greater
than that of metal oxide in micro scale [165,166]. These NPs must be
stabilized in order to inhibit their interaction with the outside en-
vironment. Nano-sized metal ions are semiconductors, affecting anti-
microbial activity based on the formation of reactive oxygen species
(ROS) [167–169]. Except ultraviolet (UV) ray, NPs are not energetic in
ROS [163,164].
As a final statement, several mechanisms have been mentioned in
respect to the antimicrobial activities of NPs. Figs. 1 and 2 shows dif-
ferent antimicrobial mechanisms mentioned for NPs. Fig. 3 display
physicochemical properties of the NPs involved in biological activity:
size, shape, surface area, chemical composition, surface chemistry, and
interactions between NPs and proteins or receptors. Also, Figs. 4 and 5
illustrate comparison of NPs-induced general toxicity via active inter-
nalization mechanisms and molecular mechanisms of ROS-mediated
cell death pathway. The common NPs used as antimicrobial agents
together with their mechanisms of action are summarized in Table 1.
Table 2 classifies antimicrobial NPs based on target microorganism and
antibacterial, antiparasite, antifungal and antiviral characteristics. In
addition, Table 3 presents a summary of NP's antiparasite activities.
Finally, Table 4 demonstrate a summary of the in vitro and in vivo
toxicity the studied NPs.
4. Cell toxicity of NPs
NPs are increasingly being used as industrial catalysts.
Unfortunately, only limited data are available regarding the environ-
mental or organismal effects of NPs. The large-scale production of NPs
inevitably risks human health, and the environment. It has been sug-
gested that NP's chemical stability significantly effects their cytotoxi-
city. NPs with oxidizing/reducing or dissolving abilities have the ca-
pacity to be toxic in cellular organisms [312]. Therefore, prudence
suggests that toxicity testing should be performed before releasing and
using such NP forms. A literature review summary of in vitro and in
vivo toxicity studies regarding NPs is presented in Table 4.
Studies reported that NPs induced oxidative stress mediates cyto-
toxicity in human cells. These NPs tend to agglomerate in the cytoplasm
and nucleus, and cause intracellular oxidative stress. For example, Both
Ag NPs, and Ag + ions induce cytotoxicity, but by different mechan-
isms [313]. Because these NPs are smaller in size, they interact with
cellular genetic material. Unfortunately, little is known about the
genotoxicity of NPs. Higher concentrations (50–100 μg/ml) stimulate
cell proliferation, while lower concentrations (1–10 μg/ml) inhibit
proliferation, and impair endothelial nitric oxide (NO) synthase
[314–316]. The entry of NPs into cells and their cytotoxicity depend
both on the type of material absorbed and their relative orientation on
nanoscale surfaces. Surface charge also affects the toxicity of NPs. This
cytotoxic response is concentration dependent. It has been suggested
that concentration-dependent electrostatic binding of these NPs on cells
results in cell lysis [317]. NPs penetrate into the human cells by un-
known mechanisms, different from phagocytosis and endocytosis. Wi-
wanitkit et al. (2009) documented that Au NPs are easily accumulated
inside white blood cells (WBCs), either via phagocytosis or direct pe-
netration [318]. NPs are used in industrial and healthcare applications.
NPs are quite small and easily penetrate through the skin by inhalation
and/or ingestion. They can be transported from nerve endings to the
skin and reach the somatosensory neurons. Indeed, toxicity is size and
concentration-dependent. High concentrations and smaller sized NPs
provide maximum toxic effects [319]. NPs induced cytotoxicity causes
519
Microbial Pathogenesis 123 (2018) 505–526
DNA damage and oxidative stress in the human cell line [320]. The
reason of toxicity induction is unclear. Despite release of ions from the
NPs, other mechanisms have also been suggested to be responsible for
toxicity. The NPs also cause oxidative lesions by significantly increasing
intracellular ROS levels [321].
Oesterling et al. (2008) reported that Al NPs induces the risk of
inflammatory diseases. Exposure to Al NPs increases level of in-
flammatory markers such as VCAM-1, ICAM-1, and ELAM-1, mRNA
level and protein expression in human umbilical vein endothelial cells.
Moreover, these NPs increase the adhesion of activated monocytes in
human endothelial cells [322]. Al NPs also induce dose-dependent
toxicity in cell lines. Exposure to lower doses of Al NPs (5–50 μg/ml),
induce little or no toxicity, whereas higher doses (100–250 μg/ml)
produce irregular cell shapes and cell shrinkage. The toxicity produced
by these NPs is independent of size and results from presence of in-
organic particles [323]. The toxicity produced by exposure to foregoing
NPs is generally resulted from chemical nature or dissolution products
and/or agglomerates.
Regarding, NPs have tendency to cause toxicity by different routes,
depending on concentration and size. It has been reported that NPs
cause abnormal sedimentation, hem-agglutination, and hemolysis in
erythrocytes [324]. Studies have shown that NPs have the tendency to
increase level of cellular nitric oxide, hydrogen peroxide, induction of
oxidative stress and inflammation-related genes and ROS in human cell
line, and are size- and shape dependent [325]. NPs also interfere with
chromosome segregation, centrosome duplication, cytokinesis, and
functional regulation of protein PLK1. Short-term exposure to NPs is
reported to enhance cell survival, cell proliferation, ERK signaling ac-
tivation, and ROS production. While, long-term exposure disrupt cell
cycle, duplicated genomes segregation, chromosomal instability, and
cell transformation in cultured human fibroblast cells [326]. NPs have
also been observed to induce apoptosis via the mitochondrial pathway
and necrosis in cultured human lymphocytes and in human mono-
blastoid cells [327]. The Easy and rapid entry of NPs, has also been
suggested as a possible reason for their toxicity [328].
Both particle types have been found to agglomerate into micro-
meter-sized particles in cell culture media, and induce toxicity through
apoptotic pathways [329].
Comparative toxicity studies have also been conducted in order to
evaluate the relative toxicity of various NPs. NPs such as ZnO have a
tendency to induce apoptosis- and necrosis-like cell death in human
astrocytoma cells and in human fibroblasts. Solubility has been found to
play a key role in the cytotoxicity of metal oxide NPs on human fi-
broblast cell lines. High soluble NPs exhibit higher toxicity [330].
However, it has been reported that NPs induce toxicity in cell mem-
branes [331]. The chemical properties of NPs also influence their cy-
totoxicity. At higher doses (100–250 m g ml−1), all NPs exhibit cyto-
toxicity which result in irregular cell shape, and cell shrinkage [332].
5. Conclusion
Several studies reported that NPs because of their biological and
physiochemical properties are promising as antimicrobials and ther-
apeutic agents. But it must be remembered that they can also possibly
led to adverse biological effects at the cellular levels. Therefore, after
the determination non-cytotoxicity and clinical studies the NPs can find
vast application as antimicrobials in the consumer and industrial pro-
ducts. Application of NPs could be considered as a proper alternative
for many antimicrobial methods. These studies suggest that NPs with
functionalized groups have enhanced antimicrobial activity and may
possibly help in eradicating microbial infections. Antimicrobial NPs
could be beneficial in the food, pharmaceutical and biomedical appli-
cations. NPs (particularly metal oxide NPs) exhibit significant anti-
microbial effects. Factors such as effectiveness of NPs on resistant
strains of microbial pathogens as well as heat resistance consider them
as potent antimicrobial agents. However, application of few NPs is
A. Khezerlou et al.
limited due to their toxicity at higher concentrations. It has also been
proposed that, ion doping and polymer incorporation of these NPs
could be useful for decreasing associated toxicity. Finally, it may be
concluded that, NPs with minimized toxicity could possibly be used in
the near future for eradicating several microorganism pathogenic and
infectious conditions. We believe that the development of simple and
low cost inorganic antimicrobial agents such as NPs as alternatives for
traditional antimicrobial agents might be promising for the future of
pharmaceutic, food and medical industry.
Conflicts of interest
The authors declare no conflict of interests.
Acknowledgments
This review was not supported by organizational and conducted at
Tabriz University of Medical Sciences, Tabriz, Iran.
Appendix A. Supplementary data
Supplementary data related to this article can be found at https://
doi.org/10.1016/j.micpath.2018.08.008.
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