Send Orders for Reprints to reprints@benthamscience.

ae
Current Topics in Medicinal Chemistry, 2015, 15, 1583-1588 1583

Molecular Mechanism and Targets of the Antimicrobial Activity of Metal

Nanoparticles

Faik N. Oktar1,2, Mehmet Yetmez3, Denisa Ficai4, Anton Ficai4, Florica Dumitru5 and
Alexandra Pica4,*

1
Department of Bioengineering, Faculty of Engineering, Marmara University, Istanbul, Turkey;
2
Nanotechnology Biomaterials Application & Research Centre, Marmara University, Istanbul, Tur-
key; 3 Mechanical Engineering Department, Faculty of Engineering, Bulent Ecevit University,
Zonguldak, Turkey; 4Politehnica University of Bucharest, Centre of Micro and Nanotechnology; 1-7 corr )

Polizu St., 011061, Bucharest, Romania; 5Research Institute for Advanced Coatings, 49 A Theodor size s

Pallady Av., Bucharest, Romania

Abstract: The emergence of multi-resistant bacteria to drugs is recognized as a major cause of the in-
creasing number of deaths in hospitals. Killing these bacteria require multiple expensive drugs that
can have side effects. Metal nanoparticles may provide a new strategy to combat them. Due the antim-
icrobial and antiviral properties, nanoparticles (NPs) have outstanding biological properties that can be handled properly
for desired applications. This review presents antibacterial and antiviral activity of metal NPs, including the molecular
mechanisms by which NPs annihilate multidrug-resistant bacteria.
Keywords: Antibacterial, Antiviral, Drug-multiresistant bacteria, Molecular mechanism.

INTRODUCTION MOLECULAR MECHANISM OF ANTIMICROBIAL

Microbial infections and development of drug resis-
tance to various pathogenic bacteria represent a major
cause of mortality [1]. The emergence in hospitals of
multidrug-resistant bacterial strains at antibiotics is increas-
ingly common [2, 3]. Before the widespread use of antibi-
otics, silver and copper have been used since ancient times
to treat microbial infections [3]. A study regarding the bac-
terial infections, presented an increase in mortality in the
case of antibiotic therapy [4, 5]. Increasing the number of
infections caused by multiresistant bacteria contributed to
the search for effective methods for dismantling drug-
resistant microorganisms [6]. Advances in nanotechnology
have led to the obtaining of a variety of materials for bio-
medical applications, including the antimicrobial [7, 8],
medicine [9], biofouling [10], etc. The most common
nanoparticles (NPs) having antimicrobial activity are silver,
titanium dioxide, zinc oxide and copper [11-15]. Metal NPs
can act on bacteria by various mechanisms. ZnO and TiO 2
NPs kill bacteria through ROS production in the presence
of UV [16-18]. Ag NPs cause damage to membrane of pro-
teins and inactivates bacteria, thus inhibiting DNA replica-
tion [19]. Although, there are many studies on the antimi-
crobial activity of metal nanoparticles, the exact mecha-
nism by which they exert damage in bacterial cells remains
unclear [20-22].
*Address correspondence to this author at the Politehnica University of
Bucharest, Centre of Micro and Nanotechnology; 1-7 Polizu St., 011061,
Bucharest, Romania; Tel: +4021-402 94 65; Fax: +4021-402 94 65;
E-mail: alexpica02@yahoo.com
METALIC NANOPARTICLES
Three hypothetical mechanisms are the most widely ac-
cepted and reported in the literature: (i) absorption of metal
ions in cells and disruption of DNA replication [23], (ii) the
generation of ROS (reactive oxygen species) from NPs and
metal ions with subsequent oxidative damage of the cellular
structures [24], and (iii) dissolution and accumulation of NPs
in the bacterial membrane that cause changes of their perme-
ability and dissipation of the proton motive force. Recently
appeared a new concept that explains the antimicrobial activ-
ity of the NPs in vivo, called "Corona". When NPs are pre-
sented in a biological environment, there is a change of their
surfaces by adsorption of biomolecules (proteins and lipids)
[25]. This concept "Corona" shows that the biological effect
of NPs depends on the type of macromolecule met and is
linked to the interaction with the cell. Changing of corona
components can occur while the nanoparticles are moving
inside the cell. This concept explains the variances that
emerge between apparently similar particles [26, 27].
MOLECULAR MECHANISM OF SILVER NANO-
PARTICLES
Antimicrobial activity of Ag NPs is explained by releas-
ing silver ions from the nanoparticles [28]. The last re-
searches carried consider that silver ions are only partially
responsible for the antibacterial effects of Ag NPs [29-32].
Rather, their properties such as the small size, surface en-
ergy, loading and solvation are relevant for the interactions
with biomolecules and their behavior in cell [25, 27, 33]. It is
assumed that the Ag NPs attach on the cell wall and pene-

1873-5294/15 $58.00+.00 © 2015 Bentham Science Publishers

1584 Current Topics in Medicinal Chemistry, 2015, Vol. 15, No. 16
trate inside of cell. Accumulation of the nanoparticles on the
cell surface causes structural changes in the cell membrane
and ultimately the death [34]. The generation of free radicals
by NPs may be another mechanism shown by studies of spin
resonance spectroscopy. These free radicals are able to dam-
age the cell membrane and cell death [28, 35, 38]. The
mechanism of antibacterial action of the silver ions is closely
related to their interaction with thiol groups (sulfhydryl-SH).
The silver ions react with the thiol group from the vital en-
zymes and inactivate them [39] or, interact with their DNA,
resulting in a markedly upsurge of pyrimidine dimers by a
photodynamic reaction or prevent the DNA replication [24,
40, 41] (Fig. 1).
Fig. (1). Mechanisms of action of the silver ions on bacteria. (1).
penetration of the bacterial cell wall; (2). silver ions are binding to
DNA blocking the ability of ribosomes to transcript messenger
RNA and to cytochrome through thiolic groups.
Schematically, the mechanism by which silver ions act
on the bacteria is as follows:
1) silver ions penetrate the bacterial cell wall and bind to the
phospholipid layer of the cytoplasmic membrane,
2) silver ions bind the bacterial DNA with subsequent dis-
rupting DNA replication,
3) silver ions impair the ability of ribosomes to transcribe
messenger RNA,
4) silver ions bind the sulfhydryl group of the cytochrome
[42, 43].
Another study suggests a novel mechanism for the anti-
bacterial effect of silver nanoparticles on Escherichia coli,
namely, the induction of a bacterial apoptosis-like response.
A possible mechanism for the bacterial apoptosis-like re-
sponse includes the following: accumulation of reactive
oxygen species (ROS), increased intracellular calcium levels,
phosphatidylserine exposure in the outer membrane and
DNA degradation [44]. Another approach to antimicrobial
activity of silver could be photocatalytic mechanism of silver
ions. These ions take part in the catalytic oxidation reactions
of the oxygen molecules from the cell and the hydrogen at-
oms in the thiol groups. Thus, two thiol groups are cova-
lently linked together by disulfide links (R-S-S-R), which
leads to blocking of respiration and the cell death [45].
MOLECULAR MECHANISM OF GOLD NANOPAR-
TICLES
Gold NPs exert mainly their antibacterial activities in two
ways: first one is to collapse membrane potential, inhibiting
Oktar et al.
ATPase activities to decrease the ATP level, second one is to
inhibit the subunit of ribosome from binding tRNA. Gold
NPs enhance chemotaxis in the early-phase reaction. [33].
Gold nanoparticles act on microorganisms through various
channels, such as disruption of the cell membrane, inhibiting
the synthesis of proteins and links with the nucleic acids [26,
46-48].
MOLECULAR MECHANISM OF COPPER NANO-
PARTICLES
Copper ions are effective catalysts of the Haber-Weiss
reaction [49, 50], leading to toxic hydroxyl radical which
causes DNA mutations [51] or damage of the cellular mac-
romolecules. Some authors have proposed antimicrobial
mechanism of Cu, but the evidence regarding the generating
of ROS in vivo is insufficient [52]. It is assumed that the
toxicity of copper is high under anaerobic conditions [52]
and ROS generation is becoming less important.
The reactive hydroxylic radicals may be generated in the
Fenton's reaction:
→ Cu 2+ + HO• + HO
Cu + + H 2 O 2 ⎯⎯
Hydroxyl radicals participate in harmful reactions for
various molecules, such as oxidation of proteins and lipids.
Copper ions can lead to depletion of the sulfhydryl groups
that is important in the stabilization of structure of protein
particles by developing sulfur bridges and in detoxification
mechanisms of the cells [53]. It is shown that the group (Fe-
S) contains some enzymes (which is essential for the func-
tion in vivo and in vitro) is destroyed by exposure to copper
and inactivate biosynthesis of amino acids [52]. The molecu-
lar mechanism of the antibacterial activity of copper is de-
rived from its atomic structure, and especially from the ex-
ternal electronic shell structure and the possibility of giving
(Cu2+) or receiving electrons easily [54]. Schematically,
mechanism of action of Cu is:
a) copper dissolves on surface and causes damages penetrat-
ing in the bacteria cells;
b) breakages of cell membrane, due to stresses caused by
copper atoms and other phenomena leading to loss of mem-
brane potential and cytoplasmic contents;
c) copper ions stimulate development of reactive oxygen
forms which causes further damages of cells;
d) genome and plasmid DNA is subject to degradation [55].
The antibacterial activity of copper could be explained by
three mechanisms: (i). increasing the concentration of copper
inside the cells produces oxidative stress and generates hy-
drogen peroxide; Cu takes part in the Fenton reaction that
causes the oxidation of cells; (ii) the excess Cu causes a de-
crease in the integrity of the membrane, which leads to leak-
age of nutrients from the cell, dehydration and cell death;
(iii) copper interacts with proteins causing the atrophy of the
functions of the proteins and/or their degradation.
MOLECULAR MECHANISM OF ALUMINA NANO-
PARTICLES
Some authors consider that the antimicrobial activity of
alumina NPs is due to the release of metal ions [56]. Alu-
Molecular Mechanism and Targets of the Antimicrobial Activity Current Topics in Medicinal Chemistry, 2015, Vol. 15, No. 16 1585

mina NPs show low antibacterial properties even at very
high concentrations. This is attributed to the surface interac-
tions between the charged particles and the cells. It is possi-
ble that there is a free radical scavenging property of the
alumina to prevent disruption of the cell wall and severe an-
timicrobial activity [57]. The mechanism of induction of
oxidative stress allows NPs to cross the barriers of cells and
to penetrate them, interacting with the sub-cellular structures
[58].
MOLECULAR MECHANISM OF MAGNESIUM OX-
IDE NANOPARTICLES
The mechanism of antimicrobial alumina is due to gen-
eration of ROS, which disrupts the cell wall (i.e. cell death).
Antibacterial mechanism of MgO NPs is not fully eluci-
dated, several mechanisms being proposed, such as: the ef-
fect of alkali [59, 60], interaction of the NPs with the bacte-
ria and their subsequent deterioration or formation of ROS.
Many studies have shown that the antibacterial mechanism
of MgO NPs is due to the formation of ROS, such as super-
oxide anion (O2 -) [60-63]. Active superoxide ions are gener-
ated on the surface of MgO and react with peptide bonds
between the cell wall and thus disturb them. Carbonyl groups
of the peptide bonds are attacked by superoxide ions and
thus protein degradation occurs [61, 64]. It is observed that
particles which are smaller than 15 nm have antimicrobial
activity due to low MgO aggregation [59, 65]. It is assumed
that the antibacterial mechanism of MgO NPs could be due
to lipid peroxidation and ROS [68, 69]. Other authors have
suggested that cell death is caused by electrostatic interaction
between the surface of bacteria and MgO nanoparticles [58,
64, 66, 67, 70].
OH radicals could be the major cause of the bactericidal ef-
fect [72] or direct oxidation with "holes" (H +) in the valence
band of the TiO2 surface [73, 74]. Reactive species attack the
cytoplasmic membrane and damage it. This membrane is
involved in cell respiration process, leading to cell death.
The main targets of oxidative attack of ROS are polyunsatu-
rated phospholipids to present in cell membranes of micro-
organisms [75]. The process of lipid peroxidation is carried
out in the presence of oxygen, and the lipid radical is con-
verted to a lipid peroxyl radical, which in turn is reacted with
an unsaturated lipid to generate a new radical and lipid. This
radical chain reaction leads to the oxidation of biomolecules
that are away from the place where attack of ROS exists [76,
77].
TARGET OF MICROORGANISM
Antibacterial Activity of Metal NPs
Metal NPs can have antibacterial, antifungal and antiviral
activity. NPs are attached to the bacteria membrane by elec-
trostatic interactions and disrupt bacterial membrane integ-
rity. The antibacterial mechanism is in particular triggered by
the induction of oxidative stress by the formation of ROS.
Table 1 shows the NPs synthesized the antibacterial activity
on Gram-positive and Gram-negative bacteria.
Table 1. Antibacterial activity of metal NPs against various
bacteria.
Type of NPs Type of bacteria Reference(s)
Gram positive bacteria

MOLECULAR MECHANISM OF ZINC OXIDE Ag, TiO2 , Cu, MgO S. aureus 32, 78-80

Some authors have proposed that the generation of hy- Halophilic bacterium
Ag, ZnO 82
drogen peroxide is to be the main mechanism of its antibac- sp.EMB4
terial activity. It is also reported that the concentration of
Vancomycin- resistant
H2O2 is linearly proportional to ZnO particle concentration Ag 83
Enterococcus
in the slurry [71, 59].
O 2 + 2e − → O −2 Ag, ZnO, Al20 3, TiO2,
B. subtilis 56, 81, 82
Cu
Subsequently, H2O2 is formed
Gram negative bacteria
O −2 + 2H + → H 2 O 2
Ag K. pneumoniae 84
These active oxygen species that react with the enzymes
present on the cell surface and inactivate them. The free elec- Ag, TiO2 , ZnO, Au P. aeruginosa 39, 84-86
trons can take part in redox reactions with the components Ag, ZnO, Al20 3, TiO2, 39, 46, 56,
from the cell surface, contributing to the distortion of the cell E. coli
MgO, Au 85, 87, 88
surface and ultimately to the inactivation of the cells. It looks
like the binding of the particles on the surface of the bacte- ZnO, TiO2 Sal. typhimurium 89
rium occurred by electrostatic forces [59].
Antiviral activity of metal NPs
MOLECULAR MECHANISM OF TITANIUM DIOX-
Metal nanoparticles interact with the genome of the virus
IDE
by interacting directly with the viral proteins from the sur-
TiO2 and ZnO NPs mainly kill bacteria via production of face [25]. NPs first enter into (i) the host cell and then (ii) the
ROS under UV irradiation. The photocatalytic mechanism is viral genome where the blocking of the cellular factors
assigned to the oxidative damage induced by ROS such as and/or the viral vectors which are important in viral replica-
O2 -, H2O2 and HO. These reactive oxygen species are pro- tion is occurred (see Table 2). NPs are alternatively attached
duced by redox reactions between adsorbed species (such as to the viral genome, so that polymerization does not occur
water and oxygen) and electron. Some authors assume that and no further formation of virions.
1586 Current Topics in Medicinal Chemistry, 2015, Vol. 15, No. 16 Oktar et al.

Table 2. Antiviral activity of metal NPs. [10] Pica, A.; Guran, C.; Ficai, D.; Ficai, A.; Oprea, O. Decorative
antimicrobial coating materials based on silver nanoparticles. UPB
Sci Bull, Series B, 2013, 75, 35-2.
[11] Bandyopadhyay, D.; Prashar, D.; Luk, Y.Y. Anti-fouling chemistry
Type of NPs Type of virus Reference(s) of chiral monolayers: enhancing biofilm resistance on racemic sur-
face. Langmuir, 2011, 27 (10), 6124-31.
Human Immunodeficiency Virus [12] Li, Q.; Mahendra, S.; Lyon, D.Y.; Brunet, L.; Liga, M.V.; Li, D.;
Ag, Au 90, 91 Alvarez, P.J. Antimicrobial nanomaterials for water disinfection
Type 1
and microbial control: potential applications and implications. Wa-
Ag, Au, ZnO Herpes Simplex Virus Type 1 92, 93 ter Res., 2008, 42 (18), 4591-02.
[13] Oprea, O.; Andronescu, E.; Ficai, D.; Ficai, A.; Oktar, F.N.; Yet-
Ag Hepatitis B Virus 94 mez, M. ZnO applications and challenges. Curr. Organic Chem.,
2014, 18, 192-03.
Ag, Au, ZnO Influenza virus 95, 96, 97 [14] Guran, C.; Pica, A.; Ficai, D.; Ficai, A.; Comanescu, C., Antimi-
crobial coatings - obtaining and characterization. Bulletin Mater.
Ag Tacaribe virus 98 Sci., 2013, 36, 183-8.
[15] Furno, F.; Morley, K.S.; Wong, B.; Sharp, B.L.; Arnold, P.L.;
Ag, TiO2 Corona virus 99, 100 Howdle, S.M.; Bayston, R.; Brown, P.D.; Winship, P.D.; Reid, H.J.
Silver nanoparticles and polymeric medical devices: a new ap-
proach to prevention of infection?, J. Antimicrob. Chemother.,
CONCLUSION AND PERSPECTIVES 2004, 54, 1019-24.
[16] Nanda, A.; Saravanan, M. Biosynthesis of silver nanoparticles from
Antibacterial properties of the metal NPs represent a Staphylococcus aureus and its antimicrobial activity against MRSA
promising alternative for destruction of bacteria with multi- and MRSE. Nanomedicine, 2009, 5, 452-56.
ple drug resistance. The targets of the NPs are external and [17] Huang, Z.; Zheng, X.; Yan, D.; Yin, G.; Liao, X.; Kang, Y.; Yao,
Y.; Huang, D.; Hao, B. Toxicological effect of ZnO nanoparticles
the internal structures of bacteria (cellular wall), plasma based on bacteria. Langmuir, 2008, 24 (8), 4140-44.
membrane, proteins and DNA. Yet, many of these molecular [18] Jones, N.; Ray, B.; Ranjit, K.T.; Manna, A.C. Antibacterial activity
mechanisms of metal NPs are not fully elucidated. Some of of ZnO nanoparticle suspensions on a broad spectrum of microor-
these NPs begin to be applied in industry, medicine, cosmet- ganisms. FEMS, Microbiol. Lett., 2008, 279, 71-6.
[19] Gou, N.; Onnis Hayden, A.; Gu, A.Z. Mechanistic toxicity assess-
ics and for this reason should be given special attention on ment of nanomaterials by whole-cell-array stress genes expression
their environmental toxicity. analysis. Environ. Sci. Technol., 2010, 44 (15), 5964-70.
[20] Su, H.; Chou, C.C.; Hung, D.J.; Lin, S.H.; Pao, I.C.; Lin, J.H.;
CONFLICT OF INTEREST Huang, F.L.; Dong, R.X.; Lin, J.J. The disruption of bacterial
membrane integrity through ROS generation induced by nanohy-
The authors confirm that this article content has no con- brids of silver and clay. Biomaterials, 2009, 30, 5979-87.
flict of interest. [21] Chaloupka, K.; Malam, Y.; Seifalian, A.M. Nanosilver as a new
generation of nanoproduct in biomedical applications. Trends Bio-
technol., 2010, 28, 580-88.
ACKNOWLEDGEMENTS [22] Choi, O.; Deng, K.K.; Kim, N.J.; Ross, L. Jr.; Surampalli, R.Y.;
Hu, Z. The inhibitory effects of silver nanoparticles, silver ions,
The work has been funded by the Sectoral Operational and silver chloride colloids on microbial growth. Water Research,
Programme Human Resources Development 2007-2013 of 2008, 42, 3066-74.
the Ministry of European Funds through the Financial [23] Reddy, K.M.; Feris, K.; Bell, J.; Wingett, D.G.; Hanley, C.; Pun-
noose, A. Selective toxicity of zinc oxide nanoparticles to prokary-
Agreement POSDRU/159/1.5/S/132395. otic and eukaryotic systems. Applied Phys. Lett., 2007. 90,
2139021-23
REFERENCES [24] Pica, A.; Ficai, D.; Guran, C. In-situ Synthesis of Nano Silver
Particles Used in Obtaining of Antimicrobial Film-Forming Mate-
[1] Kolar, M.; Urbanek, K.; Latal, T. Antibiotic selective pressure and rials. Revista De Chimie, 2012, 63, 459-62.
development of bacterial resistance. Int. J. Antimicrob. Ag., 2001, [25] Kim, J.S.; Kuk, E.; Yu, K.; Kim, J.H.; Park, S.J.; Lee, H.J.; Kim,
17, 357–63. S.H.; Park, Y.K.; Park, Y.H.; Hwang, C.Y.; Kim, Y.K.; Lee, Y.S.;
[2] Fischbach, M.A.; Walsh, C.T. Antibiotics for emerging pathogens. Jeong, D.H.; Cho, M.H. Antimicrobial effects of silver nanoparti-
Science, 2009, 325 (5944), 1089-1093. cles. Nanomedicine, 2007, 3, 95–01.
[3] Moghimi, S.M. Nanomedicine: prospective diagnostic and thera- [26] Monopoli, M.P.; Walczyk, D.; Campbell, A.; Elia, G.; Lynch, I.;
peutic potential. Asia Pacific Biotech. News, 2005, 9, 1072-77. Baldelli, B.F.; Dawson, K.A. Physical-Chemical Aspects of Protein
[4] Hu, W.B.; Peng, C.; Luo, W.J.; Lv, M.; Li, X.M.; Li, D.; Huang, Corona: Relevance to in vitro and in vivo Biological Impacts of
Q.; Fan, C. Graphene-based antibacterial paper. ACS Nano, 2010, 4 Nanoparticles. J. Am. Chem. Soc., 2011, 133 (8), 2525-34.
(7), 4317-23. [27] Walczyk, D.; Bombelli, F.B.; Monopoli, M.P.; Lynch, I.; Dawson,
[5] D'Costa, V.M.; King, C.E.; Kalan,, L.; Morar, M.; Sung, W.; K.A. What the cell “sees” in bionanoscience. J. Am. Chem. Soc.,
Schwarz, C.; Froese, D.; Zazula, G.; Calmels, F.; Debruyne, R.; 2010, 132, 5761-68.
Golding, G.B.; Poinar, H.N.; Wright, G.D. Antibiotic resistance is [28] Lundqvist, M.; Stigler, J.; Elia, G.; Lynch, I.; Cedervall, T.; Daw-
ancient. Nature, 2011, 477, 457-61. son, K.A. Nanoparticle size and surface properties determine the
[6] Ibrahim, E.H.; Sherman, G.; Ward, S.; Fraser, V.J.; Kollef, M.H. The protein corona with possible implications for biological impacts.
influence of inadequate antimicrobial treatment of bloodstream infec- Proc. Natl. Acad. Sci. USA, 2008, 105, 14265-70.
tions on patient outcomes in the ICU setting. Chest, 2000, 118, 146-55. [29] Pal, S.; Tak, Y.K.; Song, J.M. Does the antibacterial activity of
[7] Feynman, R. There's plenty of room at the bottom. Science, 1991, silver nanoparticles depend on the shape of the nanoparticle? A
254, 1300-01. study of the Gram-negative bacterium Escherichia coli. Applied
[8] Yacoby, I.; Benhar, I. Antibacterial nanomedicine. Nanomedicine, Environ. Microbiol., 2007, 73, 1712-20.
2008, 3 (3), 329-41. [30] Foldbjerg, R.; Dang, D.A.; Autrup, H. Cytotoxicity and genotoxic-
[9] Marques, C.; Ferreira, J.M.; Andronescu, E.; Ficai, D.; Sonmez, ity of silver nanoparticles in the human lung cancer cell line. A549.
M.; Ficai, A. Multifunctional materials for bone cancer treatment. Arch. Toxicol., 2011, 85, 743-50.
Int. J. Nanomedicine, 2014, 9, 2713-25. [31] Kawata, K.; Osawa, M.; Okabe, S. In vitro toxicity of silver
nanoparticles at noncytotoxic doses to HepG2 human hepatoma
cells. Environ. Sci. Technol., 2009, 43, 6046-51.
Molecular Mechanism and Targets of the Antimicrobial Activity
[32] Kim, S.; Choi, J.E.; Choi, J.; Chung, K.H.; Park, K.; Yi, J.; Ryu,
D.Y. Oxidative stress-dependent toxicity of silver nanoparticles in
human hepatomacells. Toxicol. In vitro, 2000, 9 (23), 1076-84.
[33] Krutyakov, A.; Kudrinskiy, A.; Olenin, A.Y.; Lisichkin, G.V.
Synthesis and properties of silver nanoparticles: achievements and
prospects. Uspehi Himii, 2008. 77, 242-69.
[34] Yan, C.; Yuyun, Z.; Yue, T.; Wei, Z.; Xiaoying, L.; Xingyu, J. The
molecular mechanism of action of bactericidal gold nanoparticles
on Escherichia coli. Biomaterials, 2012, 33, 2327- 33.
[35] Nedelcu, I.A.; Ficai, A.; Sonmez, M.; Ficai, D.; Oprea, O.; Andro-
nescu, E. Silver based materials for biomedical applications. Curr.
Organic Chem., 2014, 18, 173-82.
[36] Sondi, I.; Salopek-Sondi, B. Silver nanoparticles as antimicrobial
agent: a case study on E. coli as a model for Gram-negative bacte-
ria. J. Colloid Interface Sci., 2004, 275, 177–82.
[37] Pica, A.; Guran, C.; Andronescu, E.; Oprea, O.; Ficai, D.; Ficai, A.
Antimicrobial performances of some film forming materials based
on silver nanoparticles. J. Optoelectronics Adv. Mater., 2012, 14,
863-8.
[38] Kim, J.S.; Kuk, E.; Yu, K.N.; Kim, J.H.; Park, S.J.; Lee, H.J.; Kim,
S.H.; Park, Y.K.; Hwang, C.Y.; Kim, Y.K.; Lee, Y.S.; Jeong, D.H.;
Cho, M.H. Antimicrobial effects of silver nanoparticles.
Nanomedicine, 2007, 3, 95-101.
[39] Morones, J.R.; Elechiguerra, J.L.; Camacho, A.; Holt, K.; Kouri,
J.B.; Ramirez, J.T.; Yacaman, M.J. The bactericidal effect of silver
nanoparticles. Nanotechnology, 2005, 16, 2346–53.
[40] McQuillan, J.S.; Infante, G.; Stokes, E.; Shaw, A.M. Silver
nanoparticle enhanced silver ion stress response in Escherichia coli
K12. Nanotoxicology, 2012, 6, 857-66.
[41] Dragieva, I.; Stoeva, S.; Stoimenov, P.; Pavlikianov, E.; Klabunde,
K. Complex formation in solutions for chemical synthesis of
nanoscaled particles prepared by borohydride reduction process.
Nanostructured Mater., 2006, 12, 267-70.
[42] Călinescu, I.; Pătraşcu, M.; Gavrilă, A.I.; Trifan, A.; Boscornea, C.
Synthesis and characterisation of silver nanoparticles in the pres-
ence of pva and tannic acid. U.P.B. Sci. Bul., Series B, 2011, 73, 4-
12.
[43] Chudobova, D.; Maskova, D.; Kopel, P.; Merlos Rodrigo, M.A.;
Kizek, R. The effect of silver ions and silver nanoparticles on
Staphylococcus aureus. Formatex, 2013, 728-35.
[44] Ricco, J.B.; Assadian, O. Antimicrobial Silver Grafts for Preven-
tion and Treatment of Vascular Graft Infection. Semin. Vasc. Surg.,
2011, 4, 234-41.
[45] Wonyoung, L.; Keuk-Jun, K.; Dong, G.L. A novel mechanism for
the antibacterial effect of silver nanoparticles on Escherichia
coli. Biometals, 2014, 27 (6), 1191-01.
[46] Kim, J.S.; Kuk, E.; Yu, K.N.; Kim, J.H.; Park, S.J.; Lee, H.J.; Kim,
S.H.; Park, Y.K.; Park, Y.H.; Hwang, C.Y.; Kim, Y.K.; Lee, Y.S.;
Jeong, D.H.; Cho, M.H. Antimicrobial effects of silver nanoparti-
cles. Nanotech. Biol. Med., 2007, 3, 95–01.
[47] Zhao, Y.; Tian, Y.; Cui, Y.; Liu, W.; Ma, W.; Jiang, X. Small
molecule-capped gold nanoparticles as potent antibacterial agents
that target Gram-negative bacteria. J. Amer. Chem. Soc., 2010, 132
(35), 12349-56.
[48] Ma, W.; Cui, Y.; Zhao, Y.; Zheng, W.; Zhang, W.; Jiang, X.; Wen-
jie, Z. Progress of antibacterial mechanisms study on nanoparticles.
Acta Biophys Sinica, 2010, 26 (8), 638-48.
[49] Boisselier, E.; Astruc, D. Gold nanoparticles in nanomedicine:
preparations, imaging, diagnostics, therapies and toxicity. Chem.
Soc. Rev., 2009, 38 (6), 1759-82.
[50] Giljohann, D.A.; Seferos, D.S.; Daniel, W.L.; Massich, M.D.;
Patel, P.C.; Mirkin, C.A. Gold nanoparticles for biology and medi-
cine. Angew Chem. Int. Ed., 2010, 49 (19), 3280-94.
[51] Gunther, M.R.; Hanna, P.M.; Mason, R.P.; Cohen, M.S. Hydroxyl
radical formation from cuprous ion and hydrogen peroxide: a spin
trapping study. Arch. Biochem. Biophys., 1995, 316, 515-22.
[52] Tkeshelashvili, L.K.; McBride, T.; Spence, K.; Loeb, L.A. Muta-
tion spectrum of copper-induced DNA damage. J. Biol. Chem.,
1991, 266, 6401-06.
[53] Macomber, L.; Imlay, J.A. The iron-sulfur clusters of dehydratases
are primary intracellular targets of copper toxicity. Proc. Natl.
Acad. Sci. USA, 2009, 106, 8344-49.
[54] Yoshida, Y.; Furuta, S.; Niki, E. Effects of metal chelating agents
on the oxidation of lipids induced by copper and iron, Biochimica
et Biophysica Acta (BBA) – Lipids Lipid Metab., 1993, 1210/1, 81-
88
Current Topics in Medicinal Chemistry, 2015, Vol. 15, No. 16 1587
[55] Lewis, A.; Keevil, C.W. Antibacterial properties of alloys and its
alloys in HVAC&R systems. International CopperAssociation,
2004, New York.
[56] Grass, G.; Rensing, C.; Solioz, M. Metallic Copper as an Antimi-
crobial Surface. Applied Environ. Microbiol., 2011, 77 (5), 1541-
47.
[57] Jiang, W.; Mashayekhi, H.; Xing, B. Bacterial toxicity comparision
between nano- and micro- scale oxide particles. Environmental
Pollutio, 2009, 157, 1619-25
[58] Balasubramanyam, A.; Sailaja, N.; Mahboob, M.; Rahman, M.F.;
Hussain, S.M.; Grover, P. In vitro mutagenicity assessment of alu-
minium oxide nanomaterials using the Salmonella/microsome as-
say. Toxicol. in vitro, 2010, 24, 1871-76.
[59] Oberdorster, G.; Stone, V.; Donaldson, K. Toxicology of Nanopar-
ticles: A Historical Perspective. Nanotoxicology, 2007, 1, 2-25.
[60] Sawai, J. Quantitative evaluation of antibacterial activities of me-
tallic oxide powders (ZnO, MgO and CaO) by conductimetric as-
say. J. Microbiol. Methods, 2003, 54, 177-82.
[61] Yamamoto, O.; Fukuda, T.; Kimata, M.; Sawai, J.; Sasamoto, T.
Antibacterial characteristics of MgO-mounted spherical carbons
prepared by carbonization of ion-exchanged resin. J. Ceramic Soc.
Jpn., 2000, 109, 363-65.
[62] Huang, L.; Li, D.; Lin, Q.; Wei, Y.J.; Evans, M.; Duan, D.G. Con-
trollable preparation of nano-MgO and investigation of its bacteri-
cidal properties. J. Inorganic Biochem., 2005, 99, 986-93.
[63] Wang, G.; Huang, L.; Duan, X. Preparation and bactericidal prop-
erty of MgO nanoparticles on γ-Al2O3. J. Mater. Sci.: Mater.
Medicine, 2005, 16, 53-6.
[64] Yamamoto, O.; Sawai, J.; Sasamoto, T. Change in antibacterial
characteristics with doping amount of ZnO in MgO-ZnO solid so-
lution. Int. J. Inorganic Mater., 2000, 2, 451-54.
[65] Makhluf, S.; Dror, R.; Nitzan, Y.; Abramovich, Y.; Jelinek, R.;
Gedanken, A. Microwave-assisted synthesis of nanocrystalline
MgO and its use as a bacteriocide. Adv. Functional Mater., 2005,
15, 1708-15.
[66] Hewitt, C.J.; Bellara, S.T.; Andreani, A.; Nebe-von-Caron, G.;
Mcfarlane, C.M. An evaluation of the antibacterial action of ce-
ramic powder slurries using multiparameter flow cytometry. Bio-
tech. Lett., 2001, 23, 667-75.
[67] Krishnamoorthy, K.; Manivannan, G.; Kim, S.J.; Jeyasubramanian,
K.; Premanathan, M. Antibacterial activity of MgO nanoparticles
based on lipid peroxidation by oxygen vacancy. J. Nanoparticles
Res., 2012, 14, 1063-72.
[68] Leung, Y.H.; Xu, X.; Shen, Z.; Gethings, L.A.; Wong, M.T.; Chan,
C.M.; Guo, M.Y.; Djurišić, A.B.; Lee, P.K.; Chan, W.K.; Yu, L.H.;
Phillips, D.L.; Ma, A.P.; Leung, F.C. Mechanisms of antibacterial
activity of MgO: non-ROS mediated toxicity of MgO nanoparticles
towards Escherichia coli. Small. 2014, 10, 6, 1171-83.
[69] Peter, K.S.; Rosalyn, L.; George, L.M.; Klabunde, J.K. Metal oxide
nanoparticles as bactericidal agents. Langmuir, 2002, 3, 6679-86.
[70] Makhluf, S.; Dror, R.; Nitzan, Y.; Abramovich, Y.; Jelinek, R.;
Gedanken, A. Microwave-assisted synthesis of nanocrystalline
MgO and its use as a bacteriocide. Adv. Functional Mater., 2005,
15, 1708-15
[71] Stoimenov, P.K.; Klinger, R.L.; Marchin, G.L.; Klabunde, K.J.
Metal oxide nanoparticles as bactericidal agents. Langmuir, 2002,
18, 6679-8
[72] Jiang, W. Bacterial Toxicity of Oxide Nanoparticles and Their
Effects on Bacterial Surface Biomolecules, Dissertations and The-
ses. 2011.
[73] Kikuchi, Y.; Sunada, K.; Iyoda, T.; Hashimoto, K.; Fujishima, A.
Photocatalytic bactericidal effect of TiO2 thin films: Dynamic view
of the active oxygen species responsible for the effect. J. Photo-
chem. Photobiol. Chem., 1997, 106, 51–6.
[74] Nadtochenko, V.; Denisov, N.; Sarkisov, O.; Gumy, D.; Pulgarin,
C.; Kiwi, J. Laser kinetic spectroscopy of the interfacial charge
transfer between membrane cell walls of E.coli and TiO2. J. Pho-
tochem. Photobiol. Chem., 2006, 181, 401–07.
[75] Nadtochenko, V.A.; Sarkisov, O.M.; Nikandrov, V.V.; Chubukov,
P.A.; Denisov, N.N. Inactivation of Pathogenic Microorganisms in
the Photocatalytic Process on Nanosized TiO2 Crystals. Russ. J.
Phys. Chem. B. Focus Phys., 2008, 2, 105–14.
[76] Dalrymple, O.K.; Stefanakos, E.; Trotz, M.A.; Goswami, D.Y. A
review of the mechanisms and modeling of photocatalytic disinfec-
tion. Applied Catalysis B. Environ., 2010, 98, 27-8.
1588 Current Topics in Medicinal Chemistry, 2015, Vol. 15, No. 16
[77] Dalrymple, O.K.; Isaacs, W.; Stefanakos, E.; Trotz, M.A.;
Goswami, D.Y. Lipid vesicles as model membranes in photocata-
lytic disinfection studies. J. Photochem. Photobiol. a-Chem., 2011,
221, 64-70.
[78] Gupta, K.; Singh, R.P.; Pandey, A.; Pandey, A. Photocatalytic
antibacterial performance of TiO2 and Ag-doped TiO2 against S.
aureus. P. aeruginosa and E. coli. J. Nanotechnol., 2013, 4, 345–51.
[79] Ruparelia, J.P.; Chatterjee, A.K.; Duttagupta, S.P.; Mukherji, S.
Strain specificity in antimicrobial activity of silver and copper
nanoparticles. Acta Biomaterialia, 2008, 4, 3, 707–16.
[80] Baek, Y.W.; An, Y.J. Microbial toxicity of metal oxide nanoparti-
cles (CuO, NiO, ZnO, and Sb2O3) to Escherichia coli, Bacillus sub-
tilis, and Streptococcus aureus. Sci. Total Environ., 2011, 409,
1603–08.
[81] Juan, L.; Zhimin, Z.; Anchun, M.; Lei, L.; Jingchao, Z. Deposition
of silver nanoparticles on titanium surface for antibacterial effect.
Int. J. Nanomedicine., 2010, 5, 261–67.
[82] Sinha, R.; Karan, R.; Sinha, A.; Khare, S.K. Interaction and nano-
toxic effect of ZnO and Ag nanoparticles on mesophilic and halo-
philic bacterial cells. Bioresour. Technol., 2011, 102, 1516–20.
[83] Panacek, A.; Kvitek, L.; Prucek, R.; Kolar, M.; Vecerova, R.; Pi-
zurova, N.; Sharma, V.K.; Nevecna, T.; Zboril, R. Silver colloid
nanoparticles: synthesis, characterization, and their antibacterial ac-
tivity. J. Phys. Chem., 2006, 110, 16248-53.
[84] Khan, S.S.; Mukherjee, A.; Chandrasekaran, N. Studies on interac-
tion of colloidal silver nanoparticles (SNPs) with five different bac-
terial species. Colloids Surf. B: Biointerfaces, 2011, 87, 129–38.
[85] Jiang, W.; Mashayekhi, H.; Xing, B. Bacterial toxicity comparison
between nano- and micro-scaled oxide particles. Environ. Pollut.,
2009, 157, 1619–25.
[86] Feris K.; Otto, C.; Tinker, J.; Wingett, D.; Punnoose, A.; Thurber,
A.; Kongara, M.; Sabetian, M.; Quinn, B.; Hanna, C.; Pink, D.
Electrostatic interactions affect nanoparticlemediated toxicity to
gram-negative bacterium Pseudomonas aeruginosa PAO1. Lang-
muir, 2010, 26, 4429–36.
[87] Wu, B.; Huang, R.; Sahu, M.; Feng, X.; Biswas, P.; Tang, Y.J.
Bacterial responses to Cu-doped TiO2 nanoparticles. Sci. Total En-
viron., 2010, 408, 1755–58.
[88] Rispoli, F.; Angelov, A.; Badia, D.; Kumar, A.; Seal, S.; Shah, V.
Understanding the toxicity of aggregated zero valent copper
nanoparticles against Escherichia coli. J. Hazard. Mater., 2010,
180, 212–16.
Received: September 10, 2014 Revised: October 17, 2014 Accepted: January 29, 2015
Oktar et al.
[89] Kumar, A.; Pandey, A.K.; Singh, S.S.; Shanker, R.; Dhawan, A.
Cellular uptake and mutagenic potential of metal oxide nanoparti-
cles in bacterial cells. Chemosphere, 2011, 83, 1124–32
[90] Giancivincenzo, P.D.; Marradi, M.; Martinez-Avila, O.M.; Bedoya,
L.M.; Alcami, J.; Penades, S. Gold nanoparticles capped with sul-
fate-ended ligands as anti-HIV agents. Bioorg. Med. Chem. Lett.,
2010, 20, 2718–21.
[91] Lara, H.H.; Ayala-Nunez, N.V.; Turrent, L.I.; Padilla, C.R. Mode
of antiviral action of silver nanoparticles against HIV-1. J. Nano-
biotechnol., 2010, 8, 1-9.
[92] Pinto, D.B.; Shukla, S.; Perkas, N.; Gedanken, A.; Sarid, R. Inhibi-
tion of Herpes Simplex Virus Type 1 Infection by Silver Nanopar-
ticles Capped with Mercaptoethane Sulfonate. Bioconjugate Chem.,
2009, 20, 1497–02.
[93] Baram-Pinto, D.; Gedanken, A.; Sarid, R. Inhibition of HSV-1
attachment, entry, and cell-to-cell spread by functionalized multi-
valent gold nanoparticles. Small, 2010, 6 (9), 44-9.
[94] Lu, L.; Sun, R.W.; Chen, R.; Hui, C.K.; Ho, C.M.; Luk, J.M.; Lau,
G.K.; Che, C.M. Silver nanoparticles inhibit hepatitis B virus repli-
cation. Antivir. Ther., 2008, 13, 253-62.
[95] Khandelwal, N.; Kaur, G.; Kumar, N.; Tiwari, A. Application of
silver nanoparticles in viral inhibition:a new hope for antivirals.
Digest J. Nanomater. Biostructures, 2014, 9 (1), 175 - 86,
[96] Sametband, M.; Shukla, S.; Meningher, T.; Hirsh, S.; Mendelson,
E.; Sarid, R.; Gedanken, A.; Mandelboim, M. Effective multistrain
inhibition of influenza virus by anionic gold nanoparticles. Med.
Chem. Commun., 2011, 2, 421-23.
[97] Uchide, N.; Ohyama, K.; Bessho, T.; Yuan, B.; Yamakawa, T.
Effect of antioxidants on apoptosis induced by influenza virus in-
fection: inhibition of viral gene replication and transcription with
pyrrolidine dithiocarbamate. Antiviral Res., 2002, 56, 207-17.
[98] Speshock, J.L.; Murdock, R.C.; Braydich-Stolle, L.K.; Schrand,
A.M.; Hussain, S.M. Interaction of silver nanoparticles with Ta-
caribe virus. J. Nanobiotechnol., 2010, 8, 19, 1477-31
[99] Esteban, D. Mechanisms of viral emergence. Vet. Res., 2010, 41,
38-2.
[100] He, H.; Dong, X.; Yang, M.; Yang, Q.; Duan, S.; Yu, Y.; Han, J.;
Zhang, C.; Chen, L.; Yang, X. Catalytic inactivation of SARS
coronavirus, Escherichia coli and yeast on solid surface. Catal.
Commun., 2004, 5, 170-72.