The Cell Surface 10 (2023) 100112

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The Cell Surface

journal homepage: www.sciencedirect.com/journal/the-cell-surface

Alternative mechanisms of action of metallic nanoparticles to mitigate the

global spread of antibiotic-resistant bacteria
Abayeneh Girma
Department of Biology, College of Natural and Computational Science, Mekdela Amba University, P.O. Box 32, Tuluawlia, Ethiopia

A R T I C L E I N F O A B S T R A C T

Keywords: One of the biggest issues for medical professionals and a serious global concern is the emergence of multi-drug-
Nanoparticles resistant bacteria, which is the result of the overuse or misuse of antimicrobial agents. To combat this urgent
Mechanisms problem, new drugs with alternative mechanisms of action are continuously replacing conventional antimicro­
ROS
bials. Nanotechnology-fueled innovations provide patients and medical professionals with hope for overcoming
Antibiotic-resistant
Bacteria
drug resistance. The aim of the present work was to document the antimicrobial potential and mechanisms of
action of metallic nanoparticles against bacterial pathogens. Cell wall interaction and membrane penetration,
reactive oxygen species (ROS) production, DNA damage, and protein synthesis inhibition were some of the
generalised mechanisms recognised in the current study. In vitro and in vivo studies demonstrated that toxicity
concerns and the development of bacterial resistance against nanoparticles (NPs) harden the use of metallic NP
products for the treatment of drug-resistant bacterial pathogens. Therefore, researchers across the globe should
actively engage in solving the above-mentioned issues.

1. Introduction stabilising agents, and bacterial gram-type. Several studies (Abbasza­

degan et al., 2015; Almontasser et al., 2019; Dadi et al., 2019; Inam
Pathogens that have developed antibiotic resistance have become a et al., 2019; Javed et al., 2016; Saliani et al., 2015) demonstrated that,
severe health concern, and as a result, several studies have been con­ small-sized, spherical-shaped, acidic-pH, positive-charged, capped, and
ducted to enhance the effectiveness of current antimicrobial medicines high-concentration NPs and in gram-negative bacterial types had high
(Akram et al., 2022). It is also reported that over 70 % of bacterial antibacterial activity as compared to their counterparts.
diseases are resistant to one or more therapeutic agents that are Regarding mechanisms of action, metallic NPs have been shown to
commonly used to eradicate the causative agents (Dizaj et al., 2014). To have antibacterial properties in various studies; however, the precise
overcome these urgent problems, novel agents with alternative mecha­ mechanism underlying their antimicrobial action against pathogenic
nisms of action are needed for effective control of current bacterial microbes is still unknown. Numerous potential mechanisms, including
pathogens. This has sparked a lot of interest in so-called “nanotech­ nucleic acid damage, cell wall and cell membrane damage through pits
nology,” an emerging area such as the technology of production, char­ and holes, disruption of normal cell structure and function, protein
acterization, and application of materials at the nanoscale (any particle oxidation, interruption of electron transport, inhibition of cell division,
up to 100 nm). formation of reactive oxygen species (ROS), degradation or inhibition of
Nanotechnology is a novel science that is applied and benefits enzymes, inactivation or leakage of cellular materials, and loss of the
different fields of study, including medicine. A variety of metallic flagella, cellular integrity, and cellular matrix, are the antibacterial
nanoparticles (Dizaj et al., 2014; Franco et al., 2022; Malarkodi et al., mechanisms reported in the current study. Similar to the present study,
2014; Raghunath and Perumal, 2017) have drawn a lot of interest (Dakal et al., 2016) reported that the following are some of the ways that
because of their potential antimicrobial properties, including silver (Ag), metallic nanoparticles work: (i) attraction to bacterial cell walls due to
gold (Au), Ag oxide (Ag2O), zinc oxide (ZnO), titanium dioxide (TiO2), opposite surface charges; (ii) membrane instability; (iii) production of
calcium oxide (CaO), copper oxide (CuO), and magnesium oxide (MgO) reactive oxygen species (ROS); (iv) release of metal ions; and (v)
(Table 1). Even though, their antibacterial activities depend primarily modification of the signalling pathway. The unique mechanisms of
on the size, shape, surface charge, pH, concentration, type of capping or different metallic nanoparticles and their toxicity are crucial for

E-mail address: [email protected].

https://doi.org/10.1016/j.tcsw.2023.100112
Received 13 September 2023; Received in revised form 16 October 2023; Accepted 17 October 2023
Available online 20 October 2023
2468-2330/© 2023 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
A. Girma The Cell Surface 10 (2023) 100112

Table 1 2. Interaction with cellular (cell wall and membrane)

Characteristics of metallic nanoparticles and their antibacterial activities. compartments
NPs Shape Size Bacterial Time MIC References
(nm) strains Metallic NPs cling to cell walls and membranes after being exposed
ZnO Sphere- 19 E. coli 3h MIC (Li et al., to bacteria (Fig. 1). Metallic NPs’ positive surface charge is essential for
like = 2011) attachment (Wang et al., 2017). The negatively charged cell membrane
50 of the bacteria and the positively charged NPs are electrostatically
µg/ attracted to one another, making metallic NP adhesion to cell mem­
mL
TiO2 Spherical 12 E. coli MG 24 h MIC (Simon-
branes easier since they are positively charged in water. According to
1655 = Deckers research by (Z. Li et al., 2019b), positively charged magnetic (NP + )
100 et al., 2009) effectively attracted over 90 % of E. coli; however, negatively charged
µg/ magnetic (NP-) did not exhibit any affinities. These results also imply
mL
that NPs + have a high potential for electrostatically attracting bacteria.
Al2O3 Spherical 11 E. coli MG 24 h MIC (Simon-
1655 = Deckers Upon such interaction, morphological changes become obvious and can
106 et al., 2009) be distinguished by cytoplasmic shrinkage and membrane detachment,
µg/ which ultimately result in cell wall rupture (Xie et al., 2011). According
mL to transmission electron microscopy, the cell membrane of E. coli cells
Ag Spherical 7.1 E. coli MTCC 18 h MIC (Ramalingam
062 = et al., 2016)
totally ruptures after a short period of contact with AgNPs. When AgNPs
P. aeruginosa 3.6 cause damage, the cell wall becomes circumferential, and TEM images
MTCC 424 µg/ show multiple electron-dense pits at those locations. For the microor­
mL ganisms’ P. aeruginosa and S. aureus, (Song et al., 2006) demonstrated
MIC
plasmolysis and inhibition of the formation of the bacterial cell wall by
=
2.7 AgNPs. Similarly, some scholars (Leung et al., 2014; Pan et al., 2013)
µg/ have shown that MgO-NPs and Mg(OH)2-NPs can destroy cells without
mL entering the cell by electrostatic adsorption to the cell wall. In addition
Au Spherical 8.4 A. baumannii, 9h MIC (Lai et al., to electrostatic attraction, the interaction of metallic NPs with the pro­
E. coli J96, E. =8 2015)
teins in the cell wall that contain sulphur results in irreversible changes
coli O157:H7, µg/
MRSA, P. mL in cell wall structure, which causes its destruction. This, in turn, has an
aeruginosa, S. impact on the cell membrane’s permeability and lipid bilayer integrity.
aureus. Increased membrane permeability as a result of morphological changes
E. faecium MIC
in cells has an impact on their capacity to control transport activities
E. faecalis =
16 through the plasma membrane. The transport and release of potassium
µg/ (K+) ions from microbial cells can also be affected by metal ions. Simi­
mL larly, a study found that superparamagnetic iron oxide interacts with
MIC microbial cells by directly penetrating the cell membrane and inter­
fering in the transmission of transmembrane electrons. The increase in
=
32
µg/ membrane permeability may have more severe repercussions than just
mL impairing transport function, such as the loss of cellular contents
CeO2 Ellipsoidal 7 E. coli RR 13 h MIC (Thill et al., through leakage, like ions, proteins, reducing sugars, and occasionally
2006)
=
the cellular energy reserve, ATP (Dakal et al., 2016).
500
µg/
With regard to ion leaching and dissolution, several investigations
mL have shown that environmental factors, such as pH and NP dissolving
MgO Cubic 7 E. coli and S. 24 h MIC (Almontasser rate, can have a big impact on the antibacterial activity of metallic NPs.
aureus = et al., 2019) (Saliani et al., 2015), demonstrated that as pH declined from 7 to an
10
acidic pH, the inhibition of bacterial growth caused by ZnO-NPs
mg/
mL increased. Similar to this, (Moreau et al., 2007), discovered that ZnO-
Fe3O4 Spherical 66 S. aureus, S. 24 h MIC (Behera NPs dissolve more readily in acidic environments, indicating a larger
(IO) epidermis, V. = et al., 2012) release of Zn (2 + ) ions. According to (Peretyazhko et al., 2014), AgNPs
cholerae, B. 50
undergo oxidative breakdown after being discharged into the aquatic
subtilis and mg/
E. coli, Bacillus mL
system, which causes the release of Ag (+) ions and the induction of
licheniformis, antibacterial activity. They also noticed that the size-dependent disso­
Brevibacillus lution of AgNPs in acetic acid was greater than that in water.
brevis

MIC: Minimum inhibitory concentration; MRSA: Methicillin-resistant Staphy­ 3. Binding to proteins

lococcus aureus.
The alternative antibacterial mechanisms exhibited by metallic NPs
decreasing drug-resistant bacterial pathogens. Furthermore, knowing (Godoy-Gallardo et al., 2021) are protein dysfunction and enzyme
their unique mechanisms of action against the current potential drug- inactivation (Fig. 1). For example, it has been suggested that Ag (+)
resistant bacterial pathogens and their toxins is useful as a guide for primarily exerts antibacterial activity through different modes of action,
both governmental and nongovernmental policymakers and stake­ such as denaturing the 30-s ribosomal component and inhibiting the
holders to control diseases causing bacterial infections. synthesis of proteins and enzymes necessary for the production of ATP
via oxidation of amino acid side chains. For instance, protein deactiva­
tion results from persistent SAAg bonds formed when Ag (+) ions con­
nect to thiol groups of proteins present in the cell membrane. AgNPs and
Ag (+) ions interact with proteins to change their three-dimensional
(3D) structure, disrupt disulfide bonds, and block active binding sites,

2
A. Girma The Cell Surface 10 (2023) 100112

Fig. 1. The general mechanisms of metallic NPs against bacterial pathogens.

which causes general functional problems in the microorganism. effect may be due to the binding of Ag (+) ions onto the cell membrane
Furthermore, inhibition of phosphorylation of proteins would inhibit of the microbes, which consequently relays signalling and blocks the
their enzymatic activity, which in turn would result in inhibition of respiratory function of the microbes. The Ag (+) ion is known to cause
bacterial growth. Similarly, studies including the inactivation of cellular dysfunction in the respiratory electron transport chain by uncoupling it
proteins, DNA damage, and disruption of metabolic enzymes can be from oxidative phosphorylation and inhibiting respiratory chain
implicated in the beneficial antimicrobial activities of NPs (Singh et al., enzymes.
2013). This might be due to the fact that NPs have a significant potential
to inactivate common activities or metabolic processes, such as perme­ 5. Interaction with DNA
ability, respiration, and energy generation, in bacterial pathogens.
Microbial cells exposed to metallic NPs also undergo genomic al­
4. Formation of reactive oxygen species terations, such as condensation of genetic materials, particularly
genomic and plasmid DNA (Fig. 1). As a consequence, various important
Regarding ROS, it is thought that metallic NPs could enter the bac­ cellular functions get suppressed, which ultimately leads to cell necrosis
terium and inactivate the respiratory enzymes by accelerating the pro­ and death. According to (Rai et al., 2009), metallic NPs have a high
duction of free radical species such as hydrogen peroxide (H2O2), affinity for interaction with substances containing sulphur and phos­
superoxide anion (O−2 ), hydroxyl radical (HO.), hypochlorous acid phorus, such as DNA and proteins on bacterial cell membranes, alter
(HOCl), and singlet oxygen (1O2), which ultimately results in bacterial membrane permeability, damage the respiratory chain and cell division
death (Raffi et al., 2008). According to Yu et al. (Yu et al., 2020), the machinery, and ultimately cause cell death.
excessive ROS produced by nanoparticles can damage biomolecules and Furthermore, the interaction of AgNPs with DNA may result in DNA
organelle structures because of their high oxidation potential. This shearing or denaturation as well as a disruption of cell division. NP-
damage includes protein oxidative carbonylation, lipid peroxidation, induced genotoxicity includes chromosomal aberrations such as muta­
DNA/RNA breakage, enzyme inhibition, and membrane structure tions, DNA strand breaks, and oxidative DNA base damage. In E. coli,
destruction, all of which can result in necrosis, apoptosis, or even AgNPs result in DNA damage (such as strand breaks) and mutations in
mutagenesis. According to (Maji et al., 2020), ROS are very reactive crucial DNA repair genes (mutY, mutS, mutM, mutT, and nth), rendering
entities that cause damage to cell walls and membranes by breaking the mutant strains more vulnerable to AgNP-based antimicrobial treatment
carbonyl group of peptide bonds against Bacillus spp. and E. coli at an than wild-type strains (Radzig et al., 2013). The H-bonds between base
MIC of 6 and 7.5 µg/ml, respectively. Moreover, ROS are beneficial for pairs of the anti-parallel DNA strands are broken when the Ag (+) ion
increasing the gene expression levels of oxidative proteins, which is a intercalates between purine and pyrimidine base pairs, causing the
key mechanism in bacterial cell apoptosis (Fig. 1). For example, the double helical shape to be broken. In microorganisms, intercalation of
hydroxyl radical (OH.), one of the most potent radicals, is known to AgNPs in the DNA helix may prevent the transcription of some genes.
react with all components of DNA, causing single-strand breakage via Additionally, AgNPs cause the DNA molecule to transition from its
the formation of an 8-hydroxyl-2′-deoxyguanosine (8-OHdG) DNA relaxed state to its compacted shape, which impairs DNA replication.
adduct (Valavanidis et al., 2009). This could be due to the silver ions that The first stages of cell division are decreased when AgNPs connect with
AgNPs inject into the bacterial cells, increasing their bactericidal ac­ S. aureus, indicating that the interaction of the Ag (+) ions with DNA
tivity. It has also been suggested that AgNPs specifically target and may play a role in inhibiting cell division and reproduction (Jung et al.,
disrupt the respiratory chain by interacting with the thiol groups found 2008). Additionally, the bactericidal action of gold (Au) NPs against E.
in enzymes like NADH dehydrogenases, ultimately causing cell death coli was shown to involve the inhibition of ribosome subunits, in addi­
(Singh et al., 2013). As a result, it is anticipated that increasing levels of tion to the alteration of membrane and ATPase activities.
Ag (+) ions may enhance oxidative stress, which has both cytotoxic and
genotoxic effects. The rise of cellular oxidative stress in microorganisms
is a sign of the harmful effects of heavy metal ions like Ag (+). This toxic

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A. Girma The Cell Surface 10 (2023) 100112

Table 2
Toxicity effect studies of metallic nanoparticles.
Nps Dose Test organism/cell type Lab Exposed Toxic effects References
time

IO 300, 400, & 600 mg/ml C17.2 neural progenitor cells, PC12 rat In- 0, 3 & 6 Affect cell spreading and labelling and have (Soenen et al.,
pheochromocytoma cells and human blood vitro days effect on cell homeostasis. 2011)
outgrowth endothelial cells
Ag 0, 10,20, 30, 40, & 50 A549 In- 24 h Apoptosis due to ROS creation, LDH leakage, (Gurunathan
μM vitro mitochondria dysfunction, DNA fragmentation et al., 2018)
ZnO 5.6 ± 0.55, 11.75 ± Murine Cell Lines In- 24, 48, & Membrane blebbing, nuclear condensation, (Namvar et al.,
0.8, 17.45 ± 1.1, & 21.7 vitro 72 h nuclear fragmentation, and apoptotic body 2015)
± 1.3 μg/mL formation.
MgO 131.5 & 263 mg/kg Reproductive organs of rats In- 4 weeks Produced considerable changes in sex hormones (Naguib et al.,
vivo and stress parameters in both male and female 2023)
rats.
Au 72, 180, & 720 ng/mL Mammalian cell lines In- 24, 48, & DNA damage and repair responses, cell-cycle (Chueh et al.,
vitro 72 h regulation, and oxidative stress in AuNP- 2014)
induced cytotoxicity and genotoxicity effects
TiO2 20, 50, 80, 110, 140, MCF-7 In- 24, 48, & Results showed significant effect on WBC cells. (Lotfian and
170 & 200 µg/ml vitro 72 h TiO2 NPs dose and time-dependently suppressed Nemati, 2016)
the proliferation of MCF-7 cells
CuO 4, 8, 80, & 400 µg/cm2 Airway epithelial cells In- 5h Cell viability decreased in a dose-dependent (Fahmy and
vitro manner following exposure to CuO Cormier, 2009)
nanoparticles

et al., 2020; Niño-Martínez et al., 2019; Raza et al., 2021), it has been
Table 3 discovered that microbial adaptation to nanoparticles occurs through
Bacterial strains resistance evidence against some nanoparticles.
efflux pumps, electrostatic repulsion, biofilms and other extracellular
NPs Resistant Required Changes observed References polymeric materials, enzyme detoxification, volatilization, and genetic
E. coli time or
alterations (Table 3). A recent study (Kamat and Kumari, 2023) found
strains generations
that some bacterial pathogens can become resistant to antimicrobial
IO E. coli 25 days Increased cell length, (Ewunkem nanoparticles through a variety of mechanisms, including oxidative
selective sweeps in et al., 2021)
rpoA & rpoC
stress brought on by nanoparticle transformation, membrane alter­
Ag E. coli K-12 225 Mutation in cusS, purl, (Graves Jr ations, reversible adaptive resistance, irreversible alterations to cell di­
MG1655 generations rpoB, ompR et al., 2015) vision, and modifications to bacterial motility and resistance. Modify the
ZnO E. coli 25 generations Changes in cell shape- (Zhang et al., surface corona of nanoparticles, as well as strict regulation regarding the
rod to oval probably 2018)
use and disposal of nanowaste across the globe, firm knowledge of
due to low expression
of membrane protein microbe-nanoparticle interaction, and the regulated disposal of nano­
RodZ, porins particles in soil and water, are required to prevent microbes from
Ag2S E. coli ˃200 days Upregulation of MDR (M. Li et al., developing nanoparticle resistance.
genes, Cu efflux 2019a)
transporter genes
7. Conclusion

6. Current challenges and future prospects Cell wall interaction and membrane penetration, ROS production,
DNA damage, and protein synthesis inhibition were some of the
Despite the high benefits and frequent use of these particles, their generalised mechanisms recognised in the current study. This makes
specific mechanisms of toxic consequences are still unknown. The metallic NPs a promising candidate for the development of new anti­
biggest challenge is the toxicity of metallic NPs (inhaling specific NPs bacterial agents that can combat bacterial resistant pathogens. However,
may cause gene alterations, allergic reactions, or localised lung further research is needed to fully understand the potential toxicity risks
inflammation) (Table 2). When the concentration of NPs increases, it can and benefits of using metallic NPs as antibacterial agents.
lead to an increase in cytotoxicity to mammalian cells and tissues,
beneficial microbes in humans, as well as the environment (Shin et al., CRediT authorship contribution statement
2020). AgNPs are widely known for their capacity to pass the blood–­
brain barrier and accumulate in the human body and many organs, Abayeneh Girma: Conceptualization, Investigation, Writing –
particularly the brain. AgNP was additionally identified in the brain, original draft, Visualization, Writing – review & editing.
liver, kidneys, spleen, lungs, and spleen of the subjected rats (Ivask et al.,
2014). Zinc-based NPs have been demonstrated to cause toxicity, Declaration of Competing Interest
membrane damage, and increased oxidative stress in mammalian cell
lines (Saptarshi et al., 2015). To reduce the toxicity of nanoparticles in The authors declare that they have no known competing financial
human cells, it is advised to size-reduce, encapsulate, and surface- interests or personal relationships that could have appeared to influence
functionalize metallic nanoparticles. It is also advised to use in vitro the work reported in this paper.
and in vivo assessment methodologies.
Regarding bacterial resistance, it was previously believed that Acknowledgements
because NPs have a variety of ways of acting on different cell compo­
nents of bacteria, they could not quickly acquire resistance to NPs The author would like to thank all the scientists who are working to
(Amaro et al., 2021). However, recent studies have demonstrated that create a viable global healthcare system using nanoparticles.
continuous exposure to metallic nanoparticles might cause bacteria to
develop stable resistance mechanisms. According to (Gómez-Núñez

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A. Girma The Cell Surface 10 (2023) 100112

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