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302 Chemistry and Biology of Beta-Lactams
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Antibacterial Effects of Beta-Lactam
Antibiotics with Nanoparticles
Bimal Krishna Banik1 and Aparna Das
1
Department of Mathematics and Natural Sciences, College of Sciences and
Human Studies, Deanship of Research Development, Prince Mohammad
Bin Fahd University, Al Khobar 31952, Kingdom of Saudi Arabia.
2
Department of Mathematics and Natural Sciences, College of Sciences and Human Studies,
Prince Mohammad Bin Fahd University, Al Khobar 31952, Kingdom of Saudi Arabia.
*Corresponding authors: Bimal Krishna Banik, email: bimalbanik10 @gmail .c om;
bbanik @pmu .edu .sa; Aparna Das, email: aparnadasam @gmail . com
2
10.1 Introduction
In the past couple of decades, beta-lactam antibiotics (BLAs) have become the most important class of
antibacterial agents since the discovery of penicillin. It is important to note, however, that these antibacterial agents have been used in a wide range of settings, and empirical therapy has caused bacteria to
produce different kinds of beta-lactamases (β-Lases), which could lead to the spread of bacterial resistance.1, 2 As a result, it was therefore evident that BLAs had lost their clinical efcacy. Human health is
being threatened by the development of resistance to BLAs, which has become a serious problem over
the past few years.
In response to this situation, pharmaceutical researchers and medical scientists have undergone
increased pressure to develop new antibiotics. It has been reported that some approaches can be used
to overcome the resistance of bacteria. An example of this was altering the structure of beta-lactams
in such a way that they would be less susceptible to being hydrolyzed by beta-lactamases.6 The other
method was to use dual-acting cephems; this meant that if bacteria had developed resistance to one of the
antimicrobial agents, the other antimicrobial agent would act on them in a different way to kill them.7, 8
According to Vergauwe and colleagues, clavulanic acid is one of the reagents which can be used to incapacitate beta-lactamases.9 To overcome the bacterial resistance, all these methods used organic chemicals as reagents which could be added to overcome the resistance. There are only a few instances in the
antimicrobial industry where inorganic compounds or elements are used. It should be noted, however,
that inorganic nanomaterials have historically been known for their ability to eliminate microorganisms.
In recent years, nanomedicines or nano-antibiotics (NABs) have gained recognition as antibiotics
functionalized with nanoparticles have had remarkable properties that allow them to break through the
membrane barriers of bacterial cells. As compared to free antibiotic molecules, these molecules have the
intrinsic capability of reaching the target site with an increased precision and a higher level of stability
than the free antibiotic molecules. Due to the enhanced binding efciency of nanomedicines with bacterial intracellular components, nanoparticles are being utilized in a number of applications such as antibiotic delivery, membrane penetration to reach target locations, and disruption of protein synthesis. As a
result, NABs have been considered as one of the most promising alternatives to overcome antibacterial
resistance and to treat infections in clinical settings.
There are two types of nanoparticles (NPs): organic nanoparticles and inorganic nanoparticles, which
are classied according to their desired action. A variety of organic nanoparticles have been developed
3–5
304
DOI: 10.1201/9780367816339-10
305Antibacterial Effects of Beta-Lactam Antibiotics with Nanoparticles
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for a variety of treatments, including liposomes, polymeric nanoparticles, polymeric micelles, and solid
lipid nanoparticles (SLNs). There are several advantages associated with these compounds, including
biodegradability, low systemic toxicity, compatibility, and ability to handle either hydrophilic or hydrophobic drugs. Despite this, organic nanoparticles have certain limitations including poor encapsulation efciency, a short shelf life, poor stability at high temperatures, and a lack of tolerance for harsh
processing conditions. The high surface volume of inorganic nanoparticles allows them to possess
exceptional physicochemical characteristics, making them an extremely promising candidate for the
treatment of bacteria by overcoming the disadvantages resulting from antibiotics and bulk metals. It
is likely that transition metals will be the most suitable metals with which to synthesize metal-based
nanoparticles due to the fact that they have partly lled d-orbitals which confer greater redox activity, which facilitates aggregation of nanoparticles. This is supported by a series of our own studies on
tellurium-induced reactions and semiconductor in which the redox activity of the metal has played a
signicant role.
10–24
Our goal in this chapter is to discuss the antimicrobial effects of the combination of beta-lactams and
nanoparticles. Notably, our research on beta-lactams
suited to undertake a novel drug delivery program using nanoparticles.
25–40
as antibiotics and anticancer agents is well
28–34, 41–45
As well as organic
nanoparticles, inorganic nanoparticles were also taken into consideration. The information contained in
this chapter will be invaluable for the development of novel antimicrobial agents in the future.
10.2 Antibacterial Effects of Beta-Lactam Antibiotics
with Inorganic Nanoparticles
In recent years, there has been an increased interest in metallic nanoparticles due to their excellent
physical, chemical, medicinal, and catalytic properties. Nanomaterials containing metals or metal oxides
can be regarded as good inorganic nanostructures because they have performed admirably as antibiotic
resistance therapies in the past. Compared to antibiotics, nanomaterials have a different mechanism of
action, which indicates that they can be effective against pathogens that have already acquired immunity
to those antibiotics. In addition, nanoparticles are capable of targeting a wide range of biomolecules,
which is important because it inuences the genesis of antibiotic strains. During the following sections,
we will review recent reports that have been published on antibacterial synergistic effects of BLAs when
combined with metals or metal oxide nanoparticles.
10.2.1 Synergistic Antibacterial Effects of Beta-Lactam
Antibiotic Combined with Silver Nanoparticles
In comparison with all the inorganic antimicrobial agents tested, silver elements and compounds of
nanoparticles were found to be the most extensively tested. Recently, it has been discovered that silver
nanoparticles, also known as nanosilver, can be very effective antimicrobial agents against E. coli.46
Nanosilver also has excellent properties of conformational entropy in the context of versatile binding,
48
and therefore, it can easily be bonded to exible polymeric chains that are involved in the synthesis
47,
and distribution of antibiotics. Moreover, nanosilver possesses a well-developed surface chemistry, is
chemically stable, and comes in an appropriate size of 20 nm in diameter, which is 250 times smaller
than a bacterium. Despite the fact that it is in a solution, it is able to maintain a constant shape and size.
It is therefore reasonable to suggest that using nanosilver as inorganic nanomaterials in conjunction with
beta-lactams as inorganic nanomaterials against bacteria is a good idea.
The combination of BLAs and silver nanoparticles results in synergistic antibacterial effects.49 Silver
(0) nanoparticles and amoxicillin are both tested for their antibacterial activities against E. coli, respectively. In Luria–Bertani medium, increasing the concentration of both amoxicillin and silver nanoparticles showed an enhanced antibacterial effect. The bactericidal sensitivity of E. coli cells varies depending
on what antibiotics are being used. It has been proven that the combination of amoxicillin and silver
nanoparticles results in greater bactericidal effects on E. coli cells than when they are applied separately.
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As the study shows, if the amount of amoxicillin is less than 0.375 mg per ml, and the amount of
nanosilver is less than 30 μg per ml, they do not have an antimicrobial impact that is signicant. In
contrast, 0.150 mg per ml of amoxicillin plus 5 μg per ml of nanosilver can achieve the same level of
antibacterial efcacy as 0.525 mg per ml of amoxicillin or the same amount as 40 μg per ml of nanosilver
(Figure 10.1). There were no obvious effects on the growth of E. coli bacteria caused by nanoparticles
at 5 μg per ml as shown in Figure 10.2. A little delay in exponential growth and stationary phase was
observed when amoxicillin was added to a culture at 0.150 mg per ml. The results of dynamic tests on
bacterial growth have shown that the synergistic effect of amoxicillin coupled with silver nanoparticles
greatly decreases and delays the exponential and stationary phases of bacterial growth. A preincubation
with silver nanoparticles is also investigated as a method of enhancing the effects of silver nanoparticles.
It has been found that solutions with more silver nanoparticles have a greater ability to inhibit the growth
of bacteria. It has been hypothesized that this phenomenon is explained by a particular mechanism. As
shown in Fig u re 10.3, there is a possibility that nanosilver and amoxicillin may work synergistically to
kill bacteria.
As a result of the inherent architecture of biolm communities, pathogenic bacterial biolms, such as
those found in the lungs of patients with cystic brosis (CF), exhibit increased antimicrobial resistance.
FIGURE 10.1 Effect of amoxicillin and nanosilver, individually and jointly, on 5 × 106 bacterial colonies: (a) 5 μg/mL−1
nanosilver; (b) 0.150 mg/mL−1 amoxicillin; (c) 0.150 mg/m L−1 amoxicillin plus 5 μg/mL−1 nanosilver; (d) 0.150 mg/mL−1
amoxicillin plus 10 μg/mL−1 nanosilver. Adapted with permission from Li P et al. (2005).
FIGURE 10.2 Growth curve of E. coli in LB medium with 5.0 × 106 CFU without any antimicrobial agent and in the pres-
ence of amoxicillin, nanosilver, and combination of amoxicillin and nanosilver. Filled rhombus, without any antimicrobial
agent (CK); lled triangles, 5 μg/m L−1 nanosilver; lled circles, 0.150 mg/mL−1 amoxicillin; lled squares, 0.150 mg/mL−1
amoxicillin + 5 μg/mL−1 nanosilver. Adapted with permission from Li P et al. (2005).
307Antibacterial Effects of Beta-Lactam Antibiotics with Nanoparticles
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FIGURE 10.3 A diagram of the combination of nanosilver and amoxicillin reacted with cells extracellularly and inter-
cellularly. Adapted with permission from Li P et al. (2005).
By providing the antimicrobial with a barrier of protection, the biolm limits the dispersal and penetration of antimicrobials, which reduces the efcacy of antibiotics, which are normally used to inhibit the
growth of planktonic cells. It is therefore necessary to develop alternative antimicrobial strategies in
order to deal with persistent infections in the future. The antimicrobial properties of silver have been
known for decades, but silver and silver-containing compounds have recently been gaining renewed
interest as antibacterial agents for treating bacterial infections because of their antimicrobial properties. Silver nanoparticles and aztreonam have been shown to synergize when used against P. aerugi-
nosa PAO1 b i o l m s.50 The study was aimed to evaluate the effect of citrate-capped silver nanoparticles
(AgNPs) of various sizes alone as well as in combination with the monobactam antibiotic aztreonam on
P. aeruginosa PAO1 biolms and whether they were effective in inhibiting the growth of these bacteria.
Among the different sizes of AgNPs examined, 10 nm nanoparticles were most effective in inhibiting
the recovery of P. aeruginosa biolm cultures. Furthermore, 10 nm nanoparticles also showed synergy
of inhibition when combined with sub-minimum inhibitory concentration (MIC) levels of aztreonam.
Observation of biolms treated with combinations of AgNPs of 10 nm and aztreonam indicated that the
synergistic bactericidal effects are likely to result from better penetration of small AgNPs into the matrix
of the biolm, which in turn exacerbates the deleterious effects of aztreonam against the envelope of P.
aeruginosa within the biolm. As a result of these studies, it appears that small AgNPs synergistically
enhance the antimicrobial effects of aztreonam in vitro against P. aeruginosa, and this could suggest that
small AgNPs and antibiotics can be effectively combined to treat chronic infections in patients.
There is a wide array of applications in both medical and general elds relying on silver nanoparticles,
which have well-known antimicrobial properties. Synergistic effects between silver nanoparticles and
antibiotics as well as their mechanisms of action have been established. A study was conducted in which
silver nanoparticles were combined with the conventional antimicrobial agents ampicillin, chloramphenicol, and kanamycin to study the combination effects against a variety of pathogenic bacteria.51 For the
purpose of conrming antibacterial susceptibility and synergistic effects, the MIC and fractional inhibitory concentration index (FICI) were determined. As a result of these experiments, silver nanoparticles
were found to have antibacterial properties while also possessing synergistic properties.
The antibiolm activities of silver nanoparticles were also investigated, either alone or in combination with antibiotics, in order to determine if they are effective.51 There is a strong association between
the formation of biolm and the development of resistance to antimicrobial agents and chronic bacterial
infections. As a result of the study, silver nanoparticles were also found to possess antibiolm properties.
As a means of understanding the effects of silver nanoparticles, an ATPase inhibitor assay, a permeability assay, and a hydroxyl radical assay were conducted. It has been reported that the antibacterial activity
of silver nanoparticles is inuenced more by ATP-associated metabolism than by the permeability of the
outer membrane of the cells. Further, silver nanoparticles led to the production of hydroxyl radicals, a
highly reactive oxygen species (ROS) induced by bactericidal agents. Several studies conducted over the
last few years have revealed that silver nanoparticles may have potential as a combination therapeutic
agent for the treatment of infectious diseases caused by bacteria.
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In the current eld of nanotechnology research, the development of a reliable green chemistry process
for the process of biogenic synthesis of nanomaterials is viewed as one of the most important aspects
of the research. In fact, green chemistry principles in chemical research have been investigated by our
group extensively. For example, we have explored green catalytic reactions,
environmentally benign processes,
green approaches toward heterocycles.
25–27, 54–69
23, 52, 53, 85–91
natural products as anticancer drug candidates,
Therefore, an extension of our concepts on green
39, 52, 53
microwave-induced
70–84
and
chemistry to nano-drug delivery is timely and highly signicant. There have been many discoveries
made about the bactericidal and inhibitory effects of silver nanoparticles. The healthcare industry has
been facing a major challenge due to the rise of antimicrobial resistance among pathogenic bacteria
over the last few decades. A study demonstrating biogenic synthesis of silver nanoparticles that synergizes with antibiotics against both gram-positive and gram-negative bacteria has been published.92 An
investigation was carried out that examined the use of the fungus T. viride in the production of silver
nanoparticles from silver nitrate solution through extracellular biosynthesis. When exposed to a ltrate
of T. viride, it was observed that the aqueous silver ions (Ag+) were reduced in solution, thus leading to
the formation of extremely stable silver nanoparticles (AgNPs). In order to characterize these AgNPs, a
number of techniques were used. According to the UV-visible spectrum of the nanoparticles, they exhibit
maximum absorbance at 420 nm.
As a result of Fourier transform infrared (FTIR) spectroscopy, proteins were identied to be present
in the sample. In order to characterize the reduction of Ag+ ions to elemental silver, X-ray photoelectron spectrophotometry was used. The transmission electron micrograph revealed that polydispersed
nanoparticles of 5–40 nm were formed, and the presence of elemental silver was conrmed by energydispersed spectroscopy analysis. Furthermore, it was also evaluated whether the nanoparticles had
increased antimicrobial activity against gram-positive and gram-negative bacteria in combination with
various antibiotics. There was an increase in the antibacterial activity of ampicillin, kanamycin, erythromycin, and chloramphenicol in the presence of AgNPs against test strains (Table 10.1 and Figure
10.4). Ampicillin demonstrated the most pronounced enhancing effect against the test strains that were
tested. The results showed that the combination of antibiotics with AgNPs had a better antimicrobial
effect when compared to the antibiotics alone. The phenomenon was also proposed to be explained by a
mechanism (Fig u re 10.5).
It has been reported that capped silver nanoparticles increased antibacterial activity when combined
with antibiotics, on gram-negative and gram-positive bacteria in model studies.93 The nanoparticles were
prepared from AgNO3 using NaBH4 in the presence of capping agents such as citrate, sodium dodecyl
sulfate, and polyvinylpyrrolidone in this study. UV-Vis, transmittance electron microscopy (TEM), and
X-ray diffractogram (XRD) were used to characterize the nanoparticles that were formed. The generation of silver nanoparticles was veried by the appearance of a yellow color and an absorption peak
between 399 and 404 nm, which indicated that silver nanoparticles had been generated. It was found that
the nanoparticles produced were spherical in shape and polydisperse in their distribution.
XRD and SAED patterns conrm the crystallinity of the nanoparticles in the FCC structure. It was
also evaluated on model gram-negative and gram-positive bacteria, using disk diffusion assays, whether
those nanoparticles could combine their antibacterial activity with selected antibiotics (streptomycin,
ampicillin, and tetracycline) to exhibit similar antibacterial activity. All the stabilized nanoparticles
combined with the tested antibiotics were found to enhance the activity of the tested antibiotics against
both gram-positive and gram-negative bacteria when used together. As compared to citrate and sodium
dodecyl sulfate (SDS) capped nanoparticles, the combined effects of silver nanoparticles and antibiotics
were more prominent with those that were polyvinylpyrrolidone (PVP) capped. This study shows that
silver nanoparticles can be used in combination with antibiotics for the treatment of bacterial infections
with promising therapeutic effects.
10.2.2 Synergistic Antibacterial Effects of Beta-Lactam Antibiotic
Combined with Copper and Copper Oxide Nanoparticles
A copper nanoparticle (CuNP) is one of the metallic nanoparticles that have continued to gain public attention due to its optical, electrical, and thermal properties in comparison to other metallic
TABLE 10.1
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Mean Zone of Inhibition (mm) of Different Antibiotics (with and without AgNPs) Against Gram-Positive
and Gram-Negative Bacteria
Microorganisms
Erythromycin (10 μg /disk)
Fold increase
Zon e (mm) Zon e (mm)
AgNPs +
E.coli 13 16 23.08 12 16 33.33
S. typhi 24 31 29.17 13 19 46.15
S. aureus 9 10 11.11 9 11 22.22
M. luteus 8 9 12.50 10 11 10.00
Overall synergistic antibacterial effect
E. coli 22 28 27.27 12 21 75.00
S. typhi 29 36 24.14 11 20 81.82
S. aureus 9 10 11.11 11 19 72.73
M. luteus 10 11 10.00 10 17 70.00
Overall synergistic antibacterial effect
Source: Adapted with permission from Fayaz AM et al. (2010).
Erythromycin (a)
(%)
Microorganisms
Zone (mm) Zone (mm) Fold increase
Chloramphenicol(a) AgNPs +
Chloramphenicol (10 μg/d isk)
(%)
erythromyci n
(b)
chloram-
phenicol (b)
%=((b -a)/a)×10 0
18.96 Overall synergistic antibacterial
Fold increase
%=((b -a)/a)×10 0
Ampicillin(a) AgNPs +
18.13 Overall synergistic antibacterial
Kanamycin (10 μg/di sk)
Kanamycin
(a)
effect (%)
effect (%)
AgNPs +
ka na myci n( b)
Ampicillin (10 μg/disk)
ampicillin (b)
Fold increase
%=((b -a)/a)
×100
27.93
%=((b -a)/a)
×100
74.89
309Antibacterial Effects of Beta-Lactam Antibiotics with Nanoparticles
nanoparticles.94 A CuNP may be synthesized with lower costs than other materials such as silver (Ag),
gold (Au), and platinum (Pt).95 It is evident from the literature that synthesis of stable CuNPs is one of
the most challenging tasks. Numerous methods have been developed to synthesize CuNPs, including
physical, chemical, and biological methods, in order to synthesize CuNPs.96 In the past, a variety of plant
extracts have been used to synthesize copper and copper nanoparticles. Several plant extracts taken from
magnolia leaves, S. aromaticum, E. nivulia, S. urens, and latex of Euphorbiaceae have been reported to
contain biomolecules that reduce Cu ions into CuNPs.
were found to exert biological activities such as antibacterial, antioxidant, and anticancer properties.
Several studies have demonstrated that copper nanoparticles and antibiotics work synergistically in order
to enhance antibacterial activity.
The green synthesis of stable copper nanoparticles and their synergistic activity with antibiotics have
been reported in the literature.
synthesizing copper nanoparticles from green tea (C. sinensis) and beta-cyclodextrin as the raw materials. Green tea extract contains polyphenols that are responsible for the reduction of copper ions into
highly stable copper nanoparticles. Various analytical techniques were used in order to characterize
them. Copper nanoparticles exhibited a maximum absorbance at a wavelength of 659 nm in the ultraviolet-visible spectrum. Using FTIR spectroscopy, it was possible to identify the presence of polyphenols. In
order to conrm the reduction of ionic Cu to copper nanoparticles, scanning electron microscopy (SEM)
97, 98
Nanoparticles synthesized with plant extracts
101
102
A series of experiments were performed in this study with the aim of
99, 100
310 Chemistry and Biology of Beta-Lactams
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FIGURE 10.4 Percentage fold increase in antibacterial effect of antibiotics with AgNPs against test strains. Adapted with
permission from Fayaz AM et al. (2010).
FIGURE 10.5 Synergistic activity of AgNPs with ampicillin (Amp) against bacteria. (A) Formation of core silver
nanoparticles with ampicillin. (B) Interaction of AgNP-Amp complex over the cell wall of bacteria. (C) AgNP-Amp complex inhibits the formation of cross-links in the peptidoglycan layer (which provides rigidity to the cell wall), leading to
cell wall lysis. (D) AgNP-Amp complex prevents DNA unwinding. Adapted with permission from Fayaz AM et al. (2010).
and X-ray diffraction analyses were used. In addition, the nanoparticles were tested against gram-positive and gram-negative strains of bacteria in order to determine whether they were antibacterial. There
was also an evaluation of the synergistic activity of copper nanoparticles in combination with amoxicillin, ampicillin, gentamicin, and ciprooxacin. In the presence of nanoparticles, there was an increase in
the antibacterial activity of these antibiotics, which indicates that the antibiotics are more effective. The
311Antibacterial Effects of Beta-Lactam Antibiotics with Nanoparticles
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results of the study showed that combinations of antibiotics with nanoparticles have signicant antibacterial effects, particularly ampicillin, which has shown enhanced antibacterial effects.
Biolm-associated tissue and device infections are a signicant threat to the success of therapy. There
was a study which demonstrated the re-potentiation of BLAs through synergistic combination with biogenic copper oxide nanocubes, which were shown to be effective against biolm-forming multidrugresistant (MDR) bacteria.
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With the help of biologically synthesized copper oxide nanoparticles, this
work aims to improve the potency of BLAs. An evaluation of the synergistic combination of amoxyclav
and copper oxide nanoparticles against bacteria isolated from a burn wound and a urinary catheter was
carried out by means of a checkerboard assay and a time-kill assay. The control of biolm formation
and extracellular polymeric substance production by the synergistic combination was quantied in well
plate assay. The effect of copper oxide nanoparticles on the viability of human dermal broblasts was
also evaluated.
The minimum inhibitory concentration and minimum bactericidal concentration of amoxyclav were
70 µg/mL and 140 µg/mL, respectively, against P. mirabilis and 50 µg/mL and 100 µg/mL, respectively,
against S. aureus. As a result of the synergistic combination of amoxyclav with copper oxide nanoparticles, the minimum inhibitory concentration of amoxyclav was reduced by 16-fold against P. mirabilis
and 32-fold against S. aureus (Fig ure 10.6). It was found that amoxyclav, when used in conjunction with
copper oxide nanoparticles, displayed additive activity against P. mirabilis above 17.5 g/mL.
Time-kill assays showed a complete inhibition of P. mirabilis and S. aureus within 20 h and 24 h,
respectively, whereas amoxyclav and copper oxide nanoparticles did not inhibit them until 48 h (Figure
10.7 ). By combining amoxyclav with copper oxide nanoparticles, the biolm formed by P. mirabilis and
S. aureus was signicantly reduced by 85% and 93%, respectively, as a result of their synergistic action
(Figur e 10.8). The synergistic combination of amoxyclav and copper oxide nanoparticles resulted in a
signicant reduction of the concentration of proteins, carbohydrates, and DNA in the extracellular polymeric substances that make up the biolm. When broblasts were cultured with copper oxide nanoparticles, the morphology of the cells showed a normal morphology, and the viability of the cells was
99.47%. During the experiment, no cytopathic effects were observed. It has been shown, therefore, that
copper oxide nanoparticles are capable of re-potentiating amoxyclav in a manner that is highly efcient.
A green route was used to synthesize CuO and ZnO nanoparticles, and their antimicrobial activity,
cytotoxicity, as well as synergistic interaction with the antibiotic ampicillin were evaluated.
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At room
temperature, CuO and ZnO nanoparticles were synthesized by a direct, high-yield, and green method
based on a mechanically activated metathesis reaction, which yielded nanoparticles of CuO and ZnO.
FIGURE 10.6 Synergy between amoxyclav and CuO N Ps. Adapted with perm ission from Arul Selvaraj RC et al. (2019).
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