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312 Chemistry and Biology of Beta-Lactams
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FIGURE 10.7 Time-dependent destruction of bacteria by amoxyclav and CuO NPs on (a) P. mirabilis and (b) S. aureus.
Adapted with permission from Ar ul Selvaraj RC et al. (2019).
FIGURE 10.8 Inhibition of biolm formation by amoxyclav and CuO NPs. Adapted with permission from Arul Selvaraj
RC et al. (2019).
A TEM analysis showed CuO NPs to show a rodlike morphology, with average length and diameter of
22 and 6 nm, respectively, while a TEM analysis of ZnONPs showed a spherical-like morphology and a
mean diameter of 15 nm. By using the microdilution method, the antimicrobial properties of the NPs and
commercially available micrometric counterparts were evaluated to determine the minimum inhibitory
concentrations against reference strains from ATCC microorganisms, which were representative of the
main groups of bacteria related to human infections, such as E. coli, S. aureus, E. faecalis, and P. aeru-
ginosa. In comparison with the commercial micrometric particles (1000 μg/mL), the CuO and ZnONPs
showed better antibacterial properties (500 μg/mL).
It has been shown that both nanoparticles and ampicillin interact synergistically, resulting in a
decrease in their concentrations in all microorganisms studied, with ZnONPs showing the greatest synergism activity as compared to CuO NPs. However, when the antibiotic was combined with ZnONPs, the
concentrations of all microorganisms studied dropped sixfold, with the exception of P. aeruginosa. FIC
indexes were calculated for each bacterium with both NPs and ampicillin being added to it. When those
combinations were evaluated against P. aeruginosa, it was found that there was a partial synergism, but
there was also an additive effect when those combinations were evaluated. According to the results of
313Antibacterial Effects of Beta-Lactam Antibiotics with Nanoparticles
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the cell viability tests, the CuO and ZnONPs synthesized and mixed with the antibiotic are biocompatible at the effective doses (<25 μg/mL). It was found that the nanoparticles used in the study, prepared
by a green innovative synthesis, and their combination with a basic antibiotic showed interesting results,
which could lead to the possibility of one alternative to biological applications.
Various combinations of different antibiotics combined with nano-CuO have been investigated against
E. coli, and the mechanisms involved in the process have been claried.
105
CuO nanoparticles (NPs)
with 22 kinds of antibiotics were systematically tested for their combined efcacy against E. coli, and
the synergistic activities of CuO with cephalexin were identied. A range of antimicrobial susceptibility
tests were conducted, including disk diffusion tests, checkerboard methods, and time-kill tests. The CuO
nanoparticles and antibiotics were analyzed by X-ray photoelectron spectroscopy, FTIR spectroscopy,
and zeta potential to determine their interactions. For the rst time, surface plasmon resonance sensors
have been used to study the interactions between bacteria and antibacterial agents. When CuO NPs were
combined with cephalexin, a synergistic effect against E. coli was observed. As a result of increased
interaction between the concentrated cephalexin molecules and the E. coli cells, the cell walls of these
bacteria became loose. In a subsequent stage, CuO nanoparticles were able to penetrate and damage
cells more easily. Further, the presence of antibiotics did not enhance the release of Cu2+, the uptake of
Cu2+, and the generation of ROS. But the presence of cephalexin greatly enhanced cell permeability in
comparison to others.
An investigation into the synergistic antibacterial effects of copper nanoparticles when combined with
certain antibiotics against human pathogens has been reported.
106
Copper nanoparticles (CuNPs) were
synthesized by reducing an aqueous solution of copper sulfate with sodium borohydride. To analyze the
size, morphology, and quantitative information of the synthesized particles, XRD, SEM, and energydispersive spectroscopy (EDS) were used. CuNPs were tested using the agar well diffusion method to
determine if they had any antibacterial activity. By using the agar disk diffusion method, it was determined that CuNPs had a synergistic effect with broad-spectrum antibiotics. As a result of CuNPs being
applied to P. aeruginosa, the highest level of antibacterial sensitivity was recorded, whereas the least
sensitivity against S. aureus was observed. CuNPs were also able to enhance the antibacterial activity of
commercial antibiotics (penicillin, ampicillin) when they were combined with penicillin and ampicillin.
When the nanoparticles and antibiotics were taken in conjunction with the nanoparticles, the minimum
zone of inhibition was extended from 0.67 mm to 10.66 mm.
10.2.3 Synergistic Antibacterial Effects of Beta-Lactam
Antibiotic Combined with Gold Nanoparticles
Due to the surface bioconjugation with molecular probes and a number of other activities, gold nanoparticles (AuNPs) have attracted considerable interest as a new platform for many applications, including
genomics, clinical chemistry, immunoassays, optical imaging of biological cells, photothermolysis of
cancer cells, targeted delivery of genetic and immunological substances or drugs, as well as detection
and control of pathogenic microorganisms.
cles in conjunction with antibiotics and antibodies in order to selectively kill protozoa and bacteria using
photothermal methods. With regard to the antibacterial activity of gold nanoparticles, it was demonstrated that gold nanoparticles themselves do not affect bacterial growth or functional activity, whereas
conjugates of vancomycin to gold nanoparticles decrease the number of growing bacteria.
have been studies in which researchers synthesized stable gold nanoparticles covered with vancomycin
and found that this conjugate was signicantly more effective against bacteria than the free antibiotic.
A similar result has also been reported for the conjugation of ciprooxacin with Au/SiO2 core/shell
nanoparticles.
111
Scientists have been motivated by the problem of chemically synthesized nanoproducts to explore
environmentally friendly methods of nanosynthesis in order to solve this problem. A group of aquatic,
unicellular, photosynthetic microalgae called diatoms have been understudied for their potential as
reducing and capping agents for the nanosynthesis of pesticides and antibiotics in recent years. The
investigation into the mechanism of gold nanoparticle fabrication by Nitzschia diatoms and their antibacterial properties has been reported.
107
There has also been the possibility of using gold nanoparti-
108, 109
There
112
A method for fabricating bioactive gold nanoparticles using locally
110
314 Chemistry and Biology of Beta-Lactams
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isolated Nitzschia diatoms has been proposed to produce these nanoparticles in an ecofriendly manner.
The gold nanoparticles fabricated using diatoms exhibit a characteristic ruby red color with a sharp peak
in their absorbance at 529 nm. Using electron microscopy, it was conrmed that the gold nanoparticles
had irregular shapes, with an average dimension of 43 nm and a zeta potential of −16.8 mV. Through the
use of light and electron microscopy, it was possible to investigate the effects of gold nanoparticles on the
viability of diatoms. Based on the mechanism that the gold metal salt induced oxidative stress in diatoms,
it was found that exposure to gold chloride triggers elevated levels of catalase and peroxidase to relieve
ROS stress that is induced by the gold metal salt exposure.
The mechanism by which Nitzschia-mediated gold nanoparticles are fabricated was studied in detail,
and it was shown that diatom proteins, polysaccharides, are important in the reduction and stabilization
of gold nanoparticles, as evidenced by FT-IR analysis. Gold nanoparticles were shown to be bioactive
when they were coupled with antibiotics (penicillin and streptomycin), which resulted in their antibacterial activity being increased over that of individual nanoparticles and antibiotics (E. coli, P. aeruginosa,
and S. aureus). The present phyco-nanotechnological approach appears to be a promising tool that can
be used in sustainable green nanotechnology strategies as well as to reduce antibiotic use in microbial
control through the use of green nanotechnology methods.
Nanoparticles of metals are promising materials for the management of infectious diseases, as they
are known to possess a number of antimicrobial properties that are effective against pathogenic microorganisms. Because of their unique physicochemical properties, AuNPs have been used in a wide variety
of elds, including photodynamic therapy, molecular diagnostics, and drug delivery. Despite this, little
is known about the synergistic antibacterial activity of AuNPs on pathogenic bacteria as well as their
mechanism of action. It has been reported that gold nanoparticles have synergistic antibacterial activity
which is caused by apoptosis-like death of bacteria.
113
A synergistic interaction was observed between AuNPs combined with cefotaxime and ciprooxacin
against all Salmonella species; however, a combination of AuNPs combined with kanamycin did not
exhibit any synergistic interaction. In the study, it was determined that AuNPs in combination with antibiotics were able to exert their antibacterial effect on bacteria by causing apoptosis-like death in bacteria.
AuNPs caused collapse of intracellular divalent cation homeostasis, and conventional antibiotics caused
accumulation of ROS, which induced apoptotic hallmarks such as membrane depolarization, caspase‐
like proteins being activated, lamentation of cells, and externalization of phosphatidylserine. There
was a synergistic effect between the disruption of cation homeostasis by AuNPs and the accumulation of
ROS by conventional antibiotics that led to bacterial cell death and apoptosis-like death in Salmonella
colonies. Due to the synergistic effects of AuNPs and antibiotics, one can end up thinking that AuNPs
can be used as potential antibacterial agents as well as adjuvants for antimicrobial chemotherapy.
In pathogenic bacteria, antimicrobial resistance (AMR) has become a serious issue that needs to be
addressed. Vanillin-mediated green synthesis and application of gold nanoparticles in the reversal of
antimicrobial resistance in P. aeruginosa clinical isolates have been reported in the literature.
114
To
address the issue of antimicrobial resistance, the study described a green process for synthesizing vanillin-capped gold nanoparticles (VAuNPs, Figu re 10.9) using the popular avoring molecule vanillin
(C8H8O3) as a reducing agent and capping agent. As a result of physicochemical characterization, it was
discovered that the synthesized VAuNPs were stable and crystalline in nature. It was found that VAuNPs
were non-bactericidal even when they were at high concentrations (>2,000 μg/mL). The antibiotic poten-
tiation activity had been studied in combination with seven widely used antibiotics against P. aeruginosa
that was highly drug resistant. A signicant reduction in the MICs of the antibiotics meropenem (10-fold)
and trimethoprim (14-fold) was found in the presence of VAuNPs at 50 μg/mL (Table 10.2 and Figure
10.10). Additionally, it was found that VAuNPs when combined with meropenem or trimethoprim would
provide 1.5–3-fold better potentiation effects than vanillin on its own.
Based on the results of the ethidium bromide agar cartwheel assay, it was determined that VAuNPs
can block the activity of efux pumps. It was therefore concluded that the high reduction in the MICs of
antibiotics could be attributed to the efux pump repression activity of VAuNPs. Further, RT-qPCR of
clinically relevant MexAB-OprM efux pump components showed downregulation in mexB and OprM
transcripts in VAuNP-treated P. aeruginosa clinical isolates. It has been shown that VAuNPs confer
susceptibility to the last-line antibiotics, meropenem and trimethoprim, as well as a few widely used
315Antibacterial Effects of Beta-Lactam Antibiotics with Nanoparticles
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FIGURE 10.9 (a) Chemical structure of vanillin, (b) predicted structure of vanillin-capped gold nanoparticles. Adapted
with permission from Arya SS et al. (2019).
TABLE 10.2
Fold Reduction in MIC and FIC Index of Selected Antibiotics in Combination with VAuNPs, Vanillin, and
CSAuNP-Treated XDR PA11 and PA14
XDR P. aeruginosa clinical isolates
PA11 PA14
Antibiotics
Chloramphenicol 1.2 2.3 3.5 1.11 2.6 3.33
Levooxacin 1 2 2.5 1 5 5
Ciprooxacin 1 2.5 2.5 1 2.66 3.2
Tigecycline 1 2 4 1.2 3.7 5
Meropenem 1.11 6.6 10 1 1 1
Trimethoprim 1.16 4.6 14 1.33 3 4.8
Fosfomycin 1 1.2 1.2 1 1 1
Fractional inhibitory concentration index for synergic activity
Antibiotics
Chloramphenicol
Levooxacin 1.03 0.48 0.44 1.03 0.24 0.24
Ciprooxacin 1.03 0.44 0.44 1.03 0.41 0.35
Tigecycline 1.03 0.43 0.29 0.86 0.29 0.24
Meropenem 0.93 0.18 0.11 1.03 1.03 1.03
Trimethoprim 0.89 0.25 0.11 0.78 0.36 0.25
Fosfomycin 1.03 0.83 0.83 1.03 1.03 1.03
Source: Adapted with permission from Arya SS et al. (2019).
CSAuN Ps Vanillin VAu NP s CSAuNPs Vanillin VAu NP s
PA11 PA14
CSAuN Ps Vanillin VAu NP s CSAuNPs Vanillin VAuN P s
0.88 043 0.38 0.93 0.45 0.34
antibiotics, in clinical isolates of XDR P. aeruginosa that display resistance to some of these antibiotics. Hence, this study supports the idea that VAuNPs and vanillin can be used as antibiotic adjuvants
to inhibit bacterial efux pumps in order to potentiate antibiotics, thereby addressing the problem of
antimicrobial resistance that affects human health and the environment.
It was reported that green synthesis and characterization of bioinspired silver, gold, and platinum
nanoparticles, as well as the evaluation of their synergistic antibacterial activity after being combined
with different classes of antibiotics, were performed.
mentally friendly method can be used for the synthesis of silver (AgNP), gold (AuNP), and platinum
(PtNP) nanoparticles using the rind extract of the fruit of G. mangostana L. There are a variety of
115
It has been proposed that a facile and environ-
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FIGURE 10.10 SEM of P. aeruginosa (PA11): (a) untreated, (b) treated with VAuNPs 50 μg/mL, (c) meropenem 200
μg/mL, (d) meropenem and VAuNPs (20 μg/mL and 50 μg/mL, respectively), demonstrating that the addition of VAuNPs
reduced the MIC of meropenem by tenfold. Adapted with permission from Arya SS et al. (2019).
natural resources found in the fruit rind that could be easily exploited as alternatives to hazardous chemical methods used for the synthesis of nanoparticles by utilizing the rind as an alternative. The formation
of gold nanoparticles at room temperature occurred within a few seconds, whereas the formation of
silver and platinum nanoparticles occurred by heating the solution for 20 min at 80°C. For the precise
nanoparticles to be produced, it was necessary to optimize parameters such as contact time, temperature,
and pH. Several state-of-the-art analytical techniques were applied to characterize the green synthesized
nanoparticles, including UV-Vis spectroscopy, FT-IR, HR-SEM and HR-TEM, XRD analyses, and zeta
potential determinations.
A number of efforts have also been made to evaluate the antibacterial activity of metal nanoparticles
against human pathogenic bacteria before and after they have been combined with commercially available antibiotics and free antibiotics (methicillin, penicillin, azithromycin, co-trimoxazole, vancomycin, and streptomycin). The silver nanoparticles showed relatively higher antibacterial activity than the
gold nanoparticles and the platinum nanoparticles, and this antibacterial activity was more pronounced
against gram-negative bacteria than those that were gram positive. Interestingly, when the three metal
nanoparticles were combined with antibiotics, all three showed increased antibacterial activity against
the pathogenic bacteria, which suggested a synergistic effect between the nanoparticles and antibiotics.
One of the most important outcomes of the present investigation has been the fact that a strain of Bacillus
sp. that is highly resistant to streptomycin becomes highly susceptible to it when combined with gold
nanoparticles. The use of different nanoparticles in combination with antibiotic-resistant bacteria in a
clinical setting opens up a number of doors for the treatment of antibiotic-resistant bacteria.
There has been some evidence that biosynthesized gold nanoparticles combined with antibiotics have
an antibacterial synergistic effect against clinical isolates.
116
It has been determined that amoxicillin/
clavulanate (AMC) antibiotics were more effective in combination with AuNPs when used against antibiotic-resistant clinical bacterial isolates. The gold nanoparticles were synthesized using a food-derived
isolate of C. freundii (C2), which was isolated from chicken meat samples using the pour plate method
and identied using cultural characteristics and biochemical tests, and the identication to the species
level was completed using the Vitek-2 system. It was conrmed that this identication was correct by
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sequencing the 16 s rRNA. In order to achieve the nest gold nanoparticles with a diameter range of
30–60 nm, the biosynthesis of gold nanoparticles was optimized. Visual observation of the biosynthesized gold nanoparticles as well as various characterization techniques were performed on the biosynthesized gold nanoparticles: UV-VIS spectroscopy, FTIR spectroscopy analysis, atomic force microscopy
(AFM) analysis, and SEM.
A combination of AuNPs and AMC antibiotic was found to have a signicant effect against clinical
bacterial isolates when used together. Based on the results of the experiment, it was found that the biosynthesized AuNPs were roughly spherical and polydispersed. With a concentration of 62.5 µg/mL, they
were highly effective and inhibited the growth of bacteria to a signicant degree. According to the study,
the MIC value of the AMC antibiotic against clinical isolates was determined to be 500 µg/mL, whereas
the combination of gold nanoparticles with AMC had a broad spectrum of antibacterial activity against
different isolates of the bacteria that were used in the study. There was a signicant synergistic effect
between the biosynthesized gold nanoparticles when used in combination with antibiotics. As a result of
the combination, the MICs of AuNPs and AMC were less when each of them was used separately.
Using K. pneumoniae (MTCC-4030), gold nanoparticles were synthesized and characterized, and the
antibacterial and synergistic effects of the gold nanoparticles were observed.
117
To form colloidal gold
nanoparticles, gold ions in the reaction mixture were exposed to K. pneumoniae for a period of time.
There was also a peak generating at 550 nm in the UV-Vis spectral analysis of the AuNPs, according to
the characterization study. The XRD spectroscopy of the AuNPs conrmed that they are crystalline in
nature. Based on scanning electron images of the AuNPs, it was found that they were spherical in shape
and were well dispersed throughout the sample. It was determined by AFM that the AuNPs had a size
range between 10 and 15 nm. According to the results of the FTIR study, reductive groups may have been
involved in the surface of the nanoparticles. In terms of antibacterial activity, AuNPs showed the highest
inhibition zone (25.60 mm) in their investigation against E. coli, which was used as an indicator strain. It
was found that the synergistic effect of the GNPs resulted in the highest fold increase (4.06) and activity
index (3.21) against E. coli, followed by a 2.61 activity index against S. aureus, using amoxycillin and
streptomycin as standard antibiotics, respectively.
10.2.4 Synergistic Antibacterial Effects of Beta-Lactam Antibiotic
Combined with Zinc Oxide Nanoparticles
Zinc oxide is an inorganic compound with the molecular formula ZnO; it has the appearance of a white
powder, it is almost insoluble in water, and it is a nontoxic compound. As an additive, ZnO is widely used
in a wide variety of materials and products, including ceramics, glass, cement, rubber, lubricants, paints,
ointments, adhesives, plastics, sealants, pigments, foods (source of zinc nutrient), batteries, ferrites, and
retardants.
118
In the food industry, zinc oxide is used as a source of zinc, which is an essential micronutrient that plays an integral role in the growth, development, and well-being of humans as well as animals,
such as activating several enzymes, such as carbonic anhydrase, carboxypeptidase, and dehydrogenase
alcohol, in the process of the body’s metabolism. Therefore, it can be said that this compound is considered safe for use.
There has already been signicant evidence that zinc oxide nanoparticles (ZnONPs) are capable of
signicantly inhibiting the growth of bacteria in a wide range of bacteria species.
119, 120
In a number of
studies, it has been suggested that the antimicrobial properties of ZnONPs may be related to the disruption of cell membrane function and the induction of ROS, including hydrogen peroxide (H2O2), which is
detrimental to bacteria.
121
In this way, the synergistic use of antibiotics in conjunction with nanoparticles
would be a viable option to enhance the efcacy of antibiotics compared to the individual action of antibiotics used in clinical practice.
122
Over the past few years, there has been an increase in the interest in nanosized inorganic antibacterial
materials. A study has shown that ZnO nanoparticles, in combination with antibiotics, have synergistic
and antagonistic effects against a number of reference strains of pathogenic microorganisms.
122
The
purpose of this study was to determine the antimicrobial activity of silver (Ag) and zinc oxide (ZnO)
nanoparticles alone and when combined with antibiotics against a set of pathogenic microorganisms
such as S. aureus (Staph. aureus), S. enterica subsp. Bukuru, E. coli, and C. albicans.
318 Chemistry and Biology of Beta-Lactams
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With the normal disk diffusion method, the antimicrobial effect of metal nanoparticles (AgNPs
and ZnONPs) alone and in combination with antibiotics has been investigated. In both AgNPs and
ZnONPs, antibacterial activity was increased with an increase in their concentration against grampositive bacteria (Staph. aureus), gram-negative bacteria (E. coli and Salmonella spp.) and had no
effect on Candida species (albicans). In comparison to the use of antibiotics alone, a synergistic effect
of antibiotics (azithromycin, cefotaxime, cefuroxime, fosfomycin, and chloramphenicol) in the presence of AgNPs was signicantly higher when compared to the use of antibiotics alone. In the presence of AgNPs, however, all antibiotics exhibited a synergistic effect against Salmonella species.
Conversely, the antibacterial effect of AgNPs in combination with antibiotics such as oxacillin and
neomycin against Staph. aureus was signicantly reduced in comparison to the antibacterial effect of
antibiotics alone.
There was a signicant increase in the synergistic effect of antibiotics (azithromycin, oxacillin, cefotaxime, cefuroxime, fosfomycin, and oxytetracycline) compared to antibiotics alone in the presence of
ZnONPs against E. coli. In addition, the synergistic effect of antibiotics (azithromycin, cefotaxime,
cefuroxime, fosfomycin, chloramphenicol, and oxytetracycline) against the Staph. aureus was signicantly enhanced when ZnONPs were present in comparison with antibiotics alone. Alternatively, most
antibiotics had an antagonistic effect against Salmonella spp. in the presence of ZnONPs on the other
hand. ZnONPs and AgNPs both show good synergistic effects with antibiotics, which may open the door
to a future combination therapy against pathogenic bacteria using these two molecules.
As zinc oxide is a material whose properties vary according to its crystallite size or particle size, it is
often seen that nanocrystalline zinc oxide exhibits superior physical and chemical properties due to its
larger surface area and modied electron structure. There has been a study which has been published on
the synthesis of ZnO nanoparticles and an evaluation of their potential to enhance the activity of antibiot-
123
ics.
There are two different methods by which ZnO can be prepared, hydrothermal and solvothermal.
In order to characterize the sample, X-ray diffraction was used. Through the use of TEM studies, it
was further conrmed that the particles were nanosized. The average crystal size of the prepared ZnO
nanoparticles was determined by TEM analysis of the obtained samples. It was found that the synthesized nanoparticle could enhance the antibacterial efcacy of antibiotics such as ampicillin and streptomycin, which are used to treat bacteria.
In both drugs tested, it was found to be effective against the clinically important strains of bacteria
that were tested. The issue of drug resistance is an emerging crisis and one that is becoming a danger to
the public in general. Due to the increasing number of bacteria strains that are resistant to antibiotics,
the application of nanoparticles which enhance the antibacterial property will be quite useful for the
development of new drugs in the near future. Combining ZnO nanoparticles with antibiotics resulted
in an increase in the activity of antibiotics, which was observed in all the strains of bacteria tested and
was found to be effective in enhancing the activity of antibiotics. Further research may contribute to the
formulation of new drugs that can be used to inhibit the growth of drug-resistant bacteria in the future.
There is a growing problem of microbial resistance, and a search for new approaches to combat the
issue of MDR pathogens has become a necessity of the moment. It has been reported that zinc oxide
nanoparticles synthesized using C. auriculata leaf extract have synergistic antibacterial and cytotoxic
properties.
124
Using the leaf extract of C. auriculata, the study involves the green synthesis of zinc oxide
nanoparticles (ZnONPs) for the purpose of developing an antimicrobial and cytotoxic compound with
synergistic effects. Different techniques were used in order to conrm that the ZnO nanoparticles had
been formed. There is a maximum peak at 370 nm in the UV-visible spectrum of ZnONPs. The XRD
analysis of the ZnONPs conrmed that the NPs were crystalline in nature. In the SEM analysis, it was
found that the nanoparticles were spherical and irregular in shape, and their average size was 68.64 nm
(Fig u re 10 .11).
The antimicrobial activity of these compounds and the synergistic effect of these compounds have
been evaluated against various pathogenic microorganisms. It was demonstrated that ZnO nanoparticles have broad antimicrobial activity in a variety of pathogens and that they exhibit enhanced synergistic antimicrobial activity as compared to standard antibiotics (Table 10.3 and Table 10.4). ZnONPs
were evaluated for their cytotoxic effect using MTT assays on HeLa cancer cells, and it was found
that ZnONPs showed dose-dependent cytotoxic activity against these cancer cells. Synthesized ZnO
319Antibacterial Effects of Beta-Lactam Antibiotics with Nanoparticles
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FIGURE 10.11 SEM images of ZnONPs at different magnications. Adapted with permission from Kurup RS et al.
(2018).
TABLE 10.3
Synergistic Activity of ZnONPs with Different Commercial Antibiotics Against Gram-Positive Bacteria
B. subtilis B. cereus C. rubrum S. aureus
AB +
AB
Antibiotic
30
CFP
30
CEP
10
GEN
10
AMC
30
C
10
AK
30
TE
100
PB
100
AMP
Source: Adapted with permission from Padalia H et al. (2018).
AB antibiotic, a is the inhibition zones for antibiotics and b is the inhibition zones for antibiotics + ZnONPs, respectively.
ZnONPs
(a)
(b) IFA
9 15 1.77 – – – 8 7.5 – 9 – –
20.5 22 0.15 30 45 1.25 17.5 49.5 7.00 15.5 20 0.66
9.5 13.5 1.09 35 40.5 0.33 8.5 40.5 21.70 9 11 0.49
10.5 12 0.30 8 12 1.25 13 18.5 1.02 13 14.5 0.24
15 17 0.28 34.5 29.5 – 9.5 34 11.80 8 11 0.89
9.5 12.5 0.73 37.5 35.5 – 34 43.5 0.63 – – –
14.5 18.5 0.62 20.5 38 2.43 40 43.5 0.18 14.5 16.5 0.29
9.5 10.5 0.22 12 17.5 1.12 8 22.5 6.91 8 10 0.56
10 11.5 0.32 9 12 0.77 19 24 0.59 17 17 –
All values are expressed in mm. Antibiotics: cefpirome (CFP30), cephalothin (CEP30), gentamicin (GEN10), amoxyclav
(AMC10), chloramphenicol (C30), amikacin (Ak10), tetracycline (TE30), polymyxin B (PB
AB
(a)
AB +
ZnONPs
(b) IFA
AB
(a)
AB +
ZnONPs
(b) I FA
AB +
AB
ZnONPs
(a)
100
), and ampicillin (AMP10).
(b) IFA
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TABLE 10.4
Synergistic Activity of Synthesized ZnONPs with Different Commercial Antibiotics Against GramNegative Bacteria
E. coli S. typhimurium P. aerugin osa K. pneumoniae
Antibiotic
30
CFP
30
CEP
10
GEN
10
AMC
30
C
10
AK
30
TE
100
PB
100
AMP
Source: Adapted with permission from Padalia H et al. (2018).
AB
(a)
13 14 0.15 22 14.5 – 9.5 9.5 – 12.5 9.5 –
10 10 – 22.5 19 – 38.5 39.5 0.05 40.5 39.5 –
17 19.5 0.31 23 20.5 – 15.5 28 2.26 17.5 28 1.56
13 13 – 24 16 – 10.5 9 – 22 9 –
14.5 21 1.09 27.5 27.5 – 10.5 10 – 31 10 –
15.5 20.5 0.74 27.5 23 – 16 22.5 0.97 29 22.5 –
16.5 20 0.46 25 27 0.16 20 22 0.21 41 22 –
11 11.5 0.092 11 13.5 0.50 10.5 10.5 – 11 10.5 –
19.5 16.5 – 30 25.5 – 17 12 – 30.5 12 –
AB +
ZnONPs (b) IFA
AB
(a)
AB +
ZnONPs
(b) I FA
124
AB
(a)
AB +
ZnONPs
(b) IFA
AB
(a)
AB +
ZnONPs
(b) IFA
nanoparticles are highly antimicrobial and cytotoxic, due to which they can be used therapeutically for
the diagnosis and therapy of disease as nanomedicines.
When it comes to MDR microorganisms, a combination of antibiotics and nanoparticles can be used.
It has been shown that doped zinc oxide nanoparticles have synergistic effects with antibiotics such as
ciprooxacin, ampicillin, uconazole, and amphotericin B in the treatment of pathogenic microorgan-
125
isms.
With the help of standard microdilution technique, the antimicrobial activities of doped ZnO
nanoparticles (ZnONPs) were investigated against fungi and gram-positive and gram-negative bacteria.
An analysis of the interaction between the nanoparticle and the antibiotic was carried out by calculating the fractional inhibitory concentration (FIC index) of the combination through the use of checkerboard assays. The results of the experiment have demonstrated that zinc oxide nanoparticles (ZnONPs)
that were doped with 10% exhibited a maximum antimicrobial effect as compared to pure zinc oxide
nanoparticles or that were loaded with 1%.
In combination with antibiotics, an enhancement in the antimicrobial effect was observed. There were
synergistic and additive effects that were observed. There was no evidence of an antagonistic effect. The
synergistic effect of ciprooxacin was greater than ampicillin when combined. The effects of fungus
were only additive in nature. In terms of MIC results, the results are quite in line with the previous ones,
clearly demonstrating that high-doping agents are most suitable for combined therapies. It was observed
that at higher doping levels, there was a 100% synergistic interaction with ciprooxacin and ampicillin.
The study provided a preliminary report on the synergistic activity of nanoparticles with antibiotics
against different pathogenic strains of bacteria as a result of the combined treatment. This provides the
groundwork for further studies on the combination therapy of nanoparticles with antibiotics in the future.
There has been some evidence that antibiotics in combination with zinc oxide nanoparticles have a
synergistic effect against extended-spectrum beta-lactamase (ESBL) producers implicated in urinary
tract infections.
126
As part of the study, enhanced synergistic bioactivity of zinc oxide nanoparticles
(ZnONPs) in combination with BLAs has been evaluated against a panel of clinically isolated ESBL producers implicated in urinary tract infections. A series of X-ray diffraction, SEM, high-resolution TEM
(HR-TEM), selective area electron diffraction, X-ray photoelectron spectroscopy (XPS), and UV-visible
spectrophotometry techniques have been employed to characterize zinc oxide nanoparticles (15 nm) that
have been chemically synthesized. The antimicrobial potency (10 ± 0.66, 12, 11.33 ± 1.10, and 0.7 ± 0.66
mm inhibiting zone) and MICs (80, 60, 30, 50 μg/mL) of ZnONPs were tested separately, whereas timekill and membrane leakage assays were evaluated in combination with ZnONPs + cefotaxime, ampicillin, ceftriaxone, and cefepime against the beta-lactamase producer strains of E. coli, K. pneumoniae, S.
paucimobilis, and P. aeruginosa, resp ect ivel y.
321Antibacterial Effects of Beta-Lactam Antibiotics with Nanoparticles
https://t.me/med1917
The interaction of ZnO nanoparticles with BLAs and the time-kill curve dynamics of these interactions
revealed an enhanced bactericidal activity (50%, 85%, 58%, and 50% fold inhibition) by delaying the exponential and stationary phases of all isolates when tests were done separately. In order to study the effect of
post-time-kill on the cell membrane, leakage of reducing sugars and proteins was assessed in the cells. It
has been demonstrated through these assays that membrane leakage is due to the synergism of ZnONPs and
BLAs, which leads to the successful destruction of cell membranes and the death of all ESBL producers as
a result. These results indicate that ZnO nanoparticles may be used as a potentiator of BLAs in combination
therapy and thus have the potential to be used in the treatment of urinary tract infections.
10.2.5 Synergistic Antibacterial Effects of Beta-Lactam Antibiotic
Combined with Magnetic Nanoparticles
As a result of recent developments in the eld of nanotechnology applications, the need for innovative
approaches in treating bacterial infections has been highlighted. A major area of interest within the eld
of novel antibacterial therapeutics is the optimization of antibacterial effectiveness mediated by NPs.
The difference between magnetic nanoparticles (MNPs) and other investigated antibacterial nanoparticles (NPs) can be attributed to their ability to respond to external magnetic elds. Due to their magnetic
character, they can be applied to a wide variety of biomedical applications, ranging from diagnostics to
in vivo therapeutics. There is a growing interest in MNPs as a result of several factors, including their
relatively simple synthesis, intrinsic antimicrobial activity, low toxicity, and high versatility. The use
of iron oxide nanoparticles (IONPs) in biomedical applications such as in vivo drug delivery systems,
magnetic therapy-guided model, and contrast agents for magnetic resonance imaging have been widely
documented, and they have been approved by the World Health Organization for human applications.
Additionally, the antimicrobial properties of different MNPs have been demonstrated to be effective in
a number of studies.
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In recent years, core-shell MNPs have been considered promising candidates for developing new treatments against infections, including infectious diseases caused by pathogens that are resistant to antibiotics. Combined with cathelicidin LL-37 as well as selected ceragenins, core-shell MNPs displayed
synergistic antibacterial effects when used against P. aeruginosa and S. aureus.
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As part of this study,
the antibacterial peptide cathelicidin LL-37, synthetic ceragenins CSA-13 and CSA-131, as well as classical antibiotics vancomycin and colistin were assessed alone and in combination with core-shell MNPs to
assess the effectiveness of these compounds against methicillin-resistant S. aureus Xen 30 and P. aeru-
ginosa Xen 5. Microdilution method was used to determine fractional inhibitory concentration indexes
as well as fractional bactericidal concentration indexes. With the help of chemiluminescence measurements, it was possible to conrm the potential of the combined therapy using nanomaterials and selected
antibiotics. Additionally, crystal violet staining was used to evaluate the ability of the tested agents to
prevent the formation of bacterial biolms. The use of core-shell MNPs as well as ceragenins or classical antibiotics was observed to have synergistic or additive effects in most conditions. There is evidence
from the study that the combination of membrane-active agents such as LL-37 peptide or ceragenin CSA13 with MNPs might have the potential to enhance their antibacterial properties and could be considered
as a method of delaying and overcoming bacterial drug resistance.
A study has been published on the synergistic effect of functionalized MNPs and antibiotics against
S. aureus and E. coli.
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According to this study, iron oxide nanoparticles could be combined with ampicillin and gentamicin to increase their antibacterial and anti-biolm activity. Coprecipitation method
was used to synthesize lipoamino acid-coated IONs (LION14). A number of techniques were used to
characterize the LION14s. A three-time interval investigation was conducted against S. aureus and E.
coli to investigate the inhibitory activities of nanoparticles against the growth of bacteria as well as their
combined effect with ampicillin and gentamicin. The potential toxic effects of LION14 on mammalian
cell lines have been assessed by performing an in vitro cytotoxicity assay.
The detailed characterization of the LION14 has conrmed that it contains MNPs with a size of about
7 nm coated with lipo-amino acids. When ampicillin and gentamicin are combined with the appropriate concentrations of LION14s, the antimicrobial and biolm inhibiting effects of these antibiotics are
enhanced against the tested microorganisms. It was observed that ampicillin had the highest synergistic
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