Content uploaded by Kanika Rani
Author content
All content in this area was uploaded by Kanika Rani on Jun 30, 2021
Content may be subject to copyright.
Copyright © 2021 American Scientific Publishers
All rights reserved
Printed in the United States of America
Review
Journal of
Nanoscience and Nanotechnology
Vol. 21, 3495–3512, 2021
www.aspbs.com/jnn
Herbal Medicine for Urinary Tract Infections with the
Blazing Nanotechnology
Nisha Devi1, Kanika Rani1∗, Pushpa Kharb1, and Minakshi Prasad2
1Department of Molecular Biology, Biotechnology and Bioinformatics, Chaudhary Charan Singh Haryana Agricultural University,
Hisar 125004, Haryana, India
2Department of Animal Biotechnology, Lala Lajpat Rai University of Veterinary and Animal Sciences, Hisar 125001, Haryana, India
Medicinal plants have been an integral and essential part of human life since ancient times. These
have shaped the cultures around the globe. From underlings to elderly persons, everyone has come
across to use herbal medicine for minor infection to deadly diseases. A wholesome approach is
needed to maximize the knowledge about traditional resources. Thus, combining it with the new
advents of technology is miraculous. Urinary tract infections (UTIs) are among the prevalent infec-
tions in the world. Increasing multi-drug resistance among uropathogens is quite problematic. The
burning field of nanotechnology offers an enormous help in revolutionizing the diagnosis and treat-
ment of the disease. The nanoparticles and nanocarriers can increase the bioavailability and effi-
cacy of phytoconstituents targeted against the uropathogens. The present review focuses on herbal
medicine and nanomaterials like nanoparticles, nanocarriers, nanoantibiotics as potent anti-bacterial
agents against urinary tract infections.
Keywords: Medicinal Plants, Herbal Medicine, Urinary Tract Infections, Uropathogens,
Nanotechnology.
CONTENTS
1. Introduction . ....................................... 3495
2. An Overview on Classification, Transmission, Conventional Drugs,
Diagnostic and Therapeutic Approaches of UTI ............ 3497
2.1. Classification ...................................3497
2.2. Transmission of Uropathogens into Urinary Tract .......3497
2.3. Conventional Drugs forUTI .......................3497
2.4. Diagnostic and Therapeutic Approaches in Controlling UTIs3498
2.5. Conventional Therapeutic Approaches for UTIs.........3500
3. HerbalMedicine forUTIs.............................3500
4. The Nano Approach for Diagnosis and Treatment of UTIs ....3502
4.1. Nanoparticles and Nanocarriers .....................3502
4.2. Potential of Nanoparticles and Nanocarriers Against
Uropathogens . . .................................3504
4.3. Advantages and Limitations of NPs During
DrugDelivery ..................................3507
5. Conventional AntibioticsVersusNano-Antibiotics...........3508
6. Conclusion ........................................3508
Acknowledgment....................................3508
References and Notes ................................3508
1. INTRODUCTION
A urinary tract infection is any microbial invasion that
results in an inflammatory response in the epithelium of
the urinary tract [1]. It includes infection in the urethra,
∗Author to whom correspondence should be addressed.
bladder, and kidneys. Infection can occur at any age in
both the genders but more prevalent in women because of
the anatomy and reproductive physiology. Causal organ-
isms could be Bacteria, fungi, and virus but the major
one is Bacteria. Major infecting Bacteria, which accounts
for more than 95% cases is E. coli [2] while in other
cases bacteria like Klebsiella, Pseudomonas, Enterobacter,
Proteus, Staphylococcus, Mycoplasma, Chlamydia, Serra-
tia, Neisseria sp., etc are also involved. Being one of the
most common bacterial infections, UTIs affect 150 mil-
lion people worldwide [3]. In the US alone, there were
an estimated 10.5 million office visits (0.9% of all ambu-
lance visits) and 2–3 million emergency visits for UTI
symptoms [4]. It was reported that about 35% of healthy
women suffer from UTIs and 5% showed painful urination
(dysuria) [5].
There are several conventional antibiotics available for
treatment of UTIs. But the increase in antibiotic resistance
has become a major concern now-a-days, which leads
to find the other alternatives. Medicinal plants are good
candidates for potent antibacterial agents/compounds and
bioactive constituents. There are various reports available
of plants like Trachyspermum copticum, Cinnamomum
zeylanicum, Eugenia caryophyllus, Foeniculum vulgare,
J. Nanosci. Nanotechnol. 2021, Vol. 21, No. 6 1533-4880/2021/21/3495/018 doi:10.1166/jnn.2021.19002 3495
Herbal Medicine for Urinary Tract Infections with the Blazing Nanotechnology Devi et al.
and Mentha pipperita,Euphorbia hirta, Erythrophleum
suaveolens Thevetia peruviana,Agropyron repens,Zea
mays, Orthosiphon stamineus etc. which have antimicro-
bial potential against uropathogens [27, 30, 33].
These could be extracted more efficiently with the
nanotechnology and thus can provide novel and more
appropriate results. Nanotechnology also offers better
diagnosis and therapeutic tools for the treatment of
the disease. Several types of NPs like Al2O3,Fe
3O4,
Nisha Devi has obtained B.Sc. degree in Biotechnology from Feroze Gandhi Memorial
P.G. College, Mandi Adampur, Hisar in 2010 and M.Sc. degree in Biotechnology from
Guru Jambheshwar University of Science and Technology, Hisar in 2012. Currently, she
is pursuing Ph.D. degree from the Department of Molecular Biology, Biotechnology and
Bioinformatics, Chaudhary Charan Singh Haryana Agricultural University and working
under the guidance of Dr. Pushpa Kharb, Professor and Head, Department of Molecular
Biology, Biotechnology and Bioinformatics, COBS&H, CCS Haryana Agricultural Uni-
versity, Hisar, Haryana, India. She is working on, ‘Green synthesis of nanoparticles and
their biomedical applications.’
Kanika Rani has obtained B.Sc. degree in Life Sciences from D.N. College, Hisar in
2013 and M.Sc. degree in Molecular Biology and Biotechnology from Chaudhary Charan
Singh Haryana Agricultural University, Hisar in 2015. Currently, she is pursuing Ph.D.
degree from the Department of Molecular Biology, Biotechnology and Bioinformatics,
Chaudhary Charan Singh Haryana Agricultural University and working under the guidance
of Dr. Pushpa Kharb, Professor and Head, Department of Molecular Biology, Biotechnol-
ogy and Bioinformatics, COBS&H, CCS Haryana Agricultural University, Hisar, Haryana,
India. She is working on, ‘Green synthesis of nanoparticles and their biomedical applica-
tions.’
Pushpa Kharb is currently working as Head, Department of Molecular Biology and
Biotechnology, CCS Haryana Agricultural University, Hisar. She obtained her M.Sc. and
Ph.D. (Genetics) from CCS Haryana Agricultural University, Hisar. She was a Rockefeller
Foundation Post-Doctoral Fellow for two years (1997–1999) at Texas A&M University,
College Station Texas, USA. A recipient of ICAR sponsored Best Teacher award, she has
filed ten patents (of which three have been granted) in the area of Biotechnology. She held
the position of Director (T), Centre for Plant Biotechnology, New Campus, CCS HAU,
Hisar for three years (2011–2014). She has handled several National and International
research projects and has a number of publications in National and International journals
of repute to her credit.
Minakshi Prasad served as Head, Department of Animal Biotechnology, COVS, LUVAS,
Hisar, Haryana during 2013–2016 and 2018 and currently serves as Professor. She obtained
her M.V.Sc. and Ph.D. from COVS, LUVAS, Hisar. She was awarded Post Doctoral Fel-
lowship, University of Minnesota, USA, 2004 and Commonwealth Academic Staff Fel-
lowship, LSHTM, London, UK, 2009. She is recipient of International Research Ratana
Award 2019 by World Research Council; Life Time Achievement Award 2019 in Thailand
and many other awards. She is also a fellow for F-IAAVR; F-NAAS; F-NAVS; F-IAB
International Academy of Biosciences and F-SAB Society for Applied Biotechnology. She
has published 179 research papers, 24 book chapters, 3 books, 9 popular articles, and 20
scientific manuals. She has developed India’s First ever Inactivated Pentavalent Vaccine to
combat Bluetongue Disease (caused by Prototype Arbovirus) and two patents are granted
to her (Patent No. 261631 and Patent No. 261685; one applied in rotavirus diagnostics). She is a Review Editor on the
Editorial Board of Virology (specialty section of Frontiers in Microbiology and Frontiers in Plant Science) 2020.
CeO2,ZrO
2, MgO, ZnO, CuO, AgNPs, Nano-diamonds
(Carbon-based NPs, NDs), silica-titania sieves, etc. have
been synthesized using chemical and physical approaches
and targeted against various uropathogens [69–74].
In our review, we have given an overview on clas-
sification, transmission, conventional drugs, the diagnos-
tic and therapeutic approaches and herbal medicine for
UTI. We have also discussed the anti bacterial poten-
tial of nanoparticles (NPs) and nanocarriers along with
3496 J. Nanosci. Nanotechnol. 21, 3495–3512,2021
Devi et al. Herbal Medicine for Urinary Tract Infections with the Blazing Nanotechnology
their preparation and properties, targeted drug delivery for
urinary tract and benefits of Nano-antibiotics over the con-
ventional drugs. To best of our knowledge, there is no
review published on herbal medicine involved in UTI espe-
cially in context of nanotechnology.
2. AN OVERVIEW ON CLASSIFICATION,
TRANSMISSION, CONVENTIONAL
DRUGS, DIAGNOSTIC AND
THERAPEUTIC APPROACHES OF UTI
2.1. Classification
Categorization of UTI can be done on the basis of com-
plexity, site, and type of infection and the presence of
symptoms (Fig. 1). Uncomplicated UTIs affect healthy
persons with no structural or neurological abnormali-
ties [6, 7], not pregnant and not has been instrumented
(catheter-based) and apart from these, all other UTIs are
complicated [8].
Complicated UTIs occur in the persons with weak
immune defense or pregnant or having abnormalities like
urinary obstruction, urinary retention caused by neurolog-
ical disease, renal failure, renal transplantation and has
been instrumented (catheters or other drainage devices)
[9, 10]. In the US, 70–80% of complicated UTIs are
due to indwelling catheters [11], which accounts for
one million cases per year [8]. Catheter-associated UTIs
(CAUTIs) are the most common cause of secondary blood-
stream infections and are linked with high morbidity and
mortality [12].
Lower tract infection includes inflammation of the ure-
thra (urethritis) and inflammation of the urinary bladder
(cystitis) while upper tract infection includes inflamma-
tion of the kidney (pyelonephritis) and a pocket of pus in
the kidney (renal abscesses). Acute infections are associ-
ated with single pathogen while chronic are polymicrobial
involving more than one kind of bacteria or pathogen [13].
In Asymptomatic UTIs, no sign or symptoms of infection
are shown except the presence of bacteria in the urine of an
Figure 1. Classification of UTIs on the basis of different parameters.
Figure 2. Various risk factors associated with UTIs.
individual [14] and it accounts for 2–5% of young healthy
women [15] while in symptomatic lower UTI, various
signs like dysuria, frequent urination, urge to urinate with
an empty bladder, fever, flank pain [16] are shown by
patients.
There are so many reports which point out several risk
factors associated with UTIs like female gender, a previ-
ous encounter to UTI, vaginal infection, diabetes, obesity,
prolonged catheterization, old age and more (Fig. 2) [12].
2.2. Transmission of Uropathogens into Urinary Tract
Exit portal of urine, Urethra, serves as entry-way too for
uropathogens as bacteria reside around it and colonize in
urine but get washed out during micturition. The shorter
distance between urethra and bladder in case of women
makes it possible for bacteria to reach up to the blad-
der even before micturition. Also, the urethral opening is
proximate to vagina and anus, where large bacterial com-
munities are found [8].
2.3. Conventional Drugs for UTI
Globally the antibiotics like nitrofurantoin, trimethoprim-
sulfamethoxazole (TMP-SMX), fosfomycin trometa-
mol [17], pivmecillinam, fluoroquinolones (ciprofloxacin,
levofloxacin, norfloxacin), Beta-lactamase (cefdinir, cefa-
clor, cefpodoxime, amoxicillin-clavulanate), cephalexin
have been used for treatment of acute, uncomplicated
UTI, but the resistant to antibiotics is also increasing.
The extended spectrum beta-lactamase (ESBL) confers
resistant to many beta-lactam antibiotics like ampicillin
or amoxicillin [6], amoxicillin-clavulanate, penicillins,
cephalosporins, etc. because they contain an enzyme that
hydrolyzes the antibiotics [18, 19]. The ciprofloxacin,
levofloxacin (fluoroquinolones) also show increased
resistance and their consumption in older adults and
immunosuppressed patients offer high risk of tendon
rupture [20].
J. Nanosci. Nanotechnol. 21, 3495–3512, 2021 3497
Herbal Medicine for Urinary Tract Infections with the Blazing Nanotechnology Devi et al.
Several reports have confirmed that cefotaxime,
ciprofloxacin, amoxicillin, nitrofurantoin, and, etc. are
not effective against E. coli, Pseudomonas aeruginosa,
Klebsiella sp. Proteus sp. and enterobacter sp. [21–23].
Trimethoprim-sulfamethoxazole avoided during the first
trimester in the pregnant woman because it is an antago-
nist to folic acid. So, it can cause birth defects though it
is not proven in humans [24, 25].
2.4. Diagnostic and Therapeutic Approaches in
Controlling UTIs
Detection of a pathogen is a very crucial step in the treat-
ment of disease and failure of detection in early stages
could lead to lethal effects. Detection of uropathogens,
their quantification and monitoring have always been a
major focus and concern in the health care sector. Since
now several methodologies have been devised for this pur-
pose (Fig. 4).
2.4.1. Conventional Lab-Based Techniques
These methods are being used from several years and
include methods like culturing and non-culturing methods,
PCR, isothermal microcalorimetry, etc.
(A) Non-culturing methods—Culture-independent diag-
nostic techniques Offer improved turnaround times. Even
allow detection of organisms that are currently difficult or
impossible to culture and also used in combination with
the culturing method for the determination of AST. The
most common methods are
(a) Dipsticks—These are the most common point-of-
care (POC) tests for UTIs which examine the presence
of leukocytes (by leukocyte esterase activity) and nitrite
(a metabolic product of Enterobacteriaceae) in the urine
and thus indicates inflammation and bacteriuria respec-
tively. Leukocyte esterase test is based on esterolytic
activity of proteins leading to hydrolysis of ester sub-
strates [38], but it may results in false positives if urine
get contaminated with bacteria present in vaginal fluid
[39] Commonly used versions include pads to detect
blood, proteins, pH, or glucose [40]. Leukocytes gener-
ally showed high sensitivity and low specificity whereas
the opposite happens in case of nitrite.
(b) Urine microscopy—It is more labor-intensive
method than the dipstick. Pyuria is defined by at least
6–10 leukocytes in a high power field by microscopy.
In order to evaluate urine microscopy, the urine sam-
ples 1223 patients with lower UTIs were investigated
and a rapid decay in leukocytes no. up to 40% in two
hours at room temperature was observed. It was also
noticed that centrifugation and staining can not impro-
vise it, also Refrigeration or addition of boric acid leads
to loss of sensitivity [41]. A combination of nitrile test
and urine sediment microscopy can be exploited as pre-
vious lacks sensitivity and later lacks specificity and
95% sensitivity with a specificity of 41% was reported
in 1070 women with UTI symptoms. The accuracy of
urine analysis was due to bladder incubation time in
respect to bacterial counts as the duration of more than
4 hours give enough time to bacteria for multiplication
and nitrification suggesting morning urine as the sample
of choice [42].
This method can be beneficial for diagnosis along with
other methods as it differentiates gram +ve and −ve bac-
teria, but solely it can’t give concrete results [40]. Autom-
atization leading to high-throughput-screening of urine
samples prior to its cultivation may rule out negative sam-
ples as was reported in 1011 samples with a negative
predictive value (NPV) of 99.4% [43] and of 98.4% in
3443 specimens using sediMAX analyzer. It was also sug-
gested to use different algorithms for male outpatients and
patients with indwelling catheters [44].
(B) Urine culture—The severity of infection could be
estimated by this method. Specimen collection is mostly
done by clean-catch midstream technique, apart from
suprapubic aspiration and catheter technique. After the
collection of urine sample, the culturing is done within
the two hours (Fig. 3) [45]. Plating of urine specimens
obtained from patients on the suitable culture medium
along with specific supplements is of immense impor-
tance for optimum bacterial growth [46, 47]. In spite
of giving accurate results, this methodology requires
24–48 h duration for the visualization of bacterial
colonies. Thus, it would be beneficial to use it with other
methods [47].
(C) IMC (Isothermal microcalorimetry): This technique
measures the metabolic heat produced by microbes. Ther-
mopile which acts as a heat sensor captures the released
heat. The AST pattern could be assessed for several
uropathogens but six hours are required for accurate test
results with 1 extra hour for sample handling and data
analysis [48]. This technique is useful with the broad lim-
its of the volume of urine sample from nano litre to litre.
The detection limit is 10 s cells per ml within 1 h of
assay without any need for the optical clarity of sam-
ples [49]. To employ high sensitivity for the analysis, the
Figure 3. Important precautions followed during urine culture.
3498 J. Nanosci. Nanotechnol. 21, 3495–3512,2021
Devi et al. Herbal Medicine for Urinary Tract Infections with the Blazing Nanotechnology
equilibration of samples is done 1 h prior, which is a major
drawback [47].
(D) PCR and its variants—This technique can even detect
the minute concentrations of uropathogenic DNA in clin-
ical samples. With the help of primers, a large number of
uropathogens can be identified in a single PCR reaction.
Different variants like Real Time PCR, Nested PCR, Mul-
tiplex PCR and Reverse Transcriptase PCR can be used
for this purpose [50]. A smartphone-based real-time loop-
mediated isothermal amplification (smart-LAMP) system
was developed for the identification of uropathogens in
urinary sepsis patients. It was reported that results obtained
from smart-LAMP matched with the clinical diagnostics
at the admitting hospital in a fraction of the time (∼1h
vs. 18–28 h). Also, it did not show any false positives in
patients with clinically negative urine culture [51].
2.4.2. Modern Laboratory Test Techniques
Modern diagnostic platforms, including mass spectrome-
try, nucleic acid-based biosensors, microfluidics, and other
integrated approaches have been improving the diagno-
sis via direct pathogen detection from urine specimens,
expeditious AST (antimicrobial susceptibility testing), and
POC (point-of-care) testing (Fig. 4).
MALDI-TOF mass spectrometry provides a precise and
quick identification of yeast and bacteria. The Vitek MS
system has achieved FDA approval in 2013 for bacteria
detection except for Mycobacterium. But this technique is
not capable in the detection of minute bacterial conc. of
less than 104cfu/ml [52].
The biosensors use sequence-specific hybridization of
bacterial 16S rRNA for the molecular identification of
uropathogens. In UTI Sensor Array, an electrochemical
sensor array of 16 sensors, customized with bacterial spe-
cific DNA probes, is used as recognition elements and
self-assembled monolayer provide versatility in surface
modification and reduction in background noise [53, 54].
A library of DNA probes targeting the pathogens is immo-
bilized on the surface of sensors. This technique gives an
overall detection limit of 104cfu/ml, which is in com-
parison with the clinical cut off obtained during urine
Figure 4. Laboratory based diagnostic methods.
culture [55]. In a clinical study, the UTI sensor array pro-
vided 92% overall sensitivity and 97% specificity as com-
pared to urine culture for pathogen detection [55, 56].
The DNA microarray technology provides an accurate
and rapid diagnosis and absolute treatment in associa-
tion with UTIs caused by the pathotypes of uropathogenic
E. coli (UPEC). The UPEC virulence genes can be
used for designing the appropriate DNA microarray
probes [57]. The integration of the 16S rRNA gene (16S
rDNA) sequencing with metaproteomics can be beneficial
for the prevention and treatment of UTI as it improves
the knowledge regarding healthy urine microbiome. In a
study, this approach was used in the differentiation of
healthy urine microbiome from asymptomatic bacteriuria
in the neuropathic bladder (NB) associated with spinal
cord injury and it was reported that healthy urine is not
sterile and could be altered by method of urinary catheter-
ization, presence, and duration of NB [58].
Microfluidics involves the manipulation of reagents and
analytes at the micron scale. This is an ideal technique
for sample preparation as it requires low reagent and sub-
strate volume. It also offers features like laminar fluid
flow, fast thermal relaxation and reduced assay time [59].
Various microfluidic designs have been initiated to exe-
cute on-chip serial dilutions of drugs by using either
magnetofluidic droplet fusion [60] or parallel channels
as a sink-and-source system for gradient generation [61]
and microvalve-based multiplex channels for mixing [62].
The implementation of these devices in clinical settings
demands improved accessibility and automation. More-
over, different platforms might prove to be optimal for
different clinical settings [63].
2.4.3. Immunological Based Methods
These methods mainly rely upon affinity between antibody
and antigen or between complementary DNA molecules.
ELISA (enzyme-linked immunosorbent assay) is being
widely utilized for identification of uropathogenic compo-
nents in biological samples [47] and among all the other
variants, sandwich ELISA is the most practiced. The major
limitations include long incubation period for each step
and lesser sample volume accommodation on microtitre
plate [64]. Various assays like immunoenzymatic assay,
coagglutination (Co-A), latex agglutination are also used
for this purpose. But some drawbacks are associated with
these techniques like non-specific agglutination reaction of
latex particles [65] and low sensitivity of Co-A in the case
of lower amount of antigen in the urine sample [66].
The diagnosis can be improved by merging immuno-
logical assays with the modern platforms. The identifica-
tion and evaluation of the uropathogenic bacteria could be
employed on a cell-based LOC (lab-on-a-chip) system by
IATP-BLA (immunosorbent ATP-bioluminescence assay).
The specific antibodies present on the fiberglass membrane
are used for capturing of the target microbes present in the
J. Nanosci. Nanotechnol. 21, 3495–3512, 2021 3499
Herbal Medicine for Urinary Tract Infections with the Blazing Nanotechnology Devi et al.
urine samples. Then the in situ encapsulation of these fixed
targets is done by calcium alginate. Their survival for on-
chip AST is due to availability of growth medium. After
this, the bioluminescence assay is performed. The amount
of microbes present in the urine sample is proportional to
the magnitude of ATP-bioluminescence signal. The 384-
chambered microfluidic simulator is used as the integration
platform and it provides the specificity and ultra-sensitivity
to the assay. This entire set up can perform an AST of
8 selected antibiotics on 13 different types of microbial
strains in minutes or in a very few hours as compared to
the test cycle of a traditional microbial culture [67].
2.5. Conventional Therapeutic Approaches for UTIs
The conventional approaches associated with the treatment
of UTIs are the use of antibiotics or drugs, immunothera-
peutics, Lactobacillus preparations, functional food prod-
ucts, vaccines, etc. Among these, the most common
approach is the use of antibiotics or drugs. The antibiotics
like nitrofurantoin, trimethoprim-sulfamethoxazole (TMP-
SMX), fosfomycin trometamol [17], fluoroquinolones
(ciprofloxacin, levofloxacin, norfloxacin), Beta-lactamase
(cefdinir, cefaclor, cefpodoxime, amoxicillin-clavulanate),
cephalexin have been used for treatment of acute, uncom-
plicated UTI around the globe. But the increase in
antibiotic resistance has become a major concern now-
a-days. Several reports have confirmed that cefotaxime,
ciprofloxacin, amoxicillin, nitrofurantoin, and, etc. are not
effective against E. coli, Pseudomonas aeruginosa, Kleb-
siella sp. Proteus sp. and Enterobacter sp. [21–23].
Among food products, the American Cranberry is the
best studied natural therapeutic. The clinical trials for it
with various formulations have been analyzed [87–89].
While some other preparations involving food products
like rice vinegar [90], garlic (for non E. coli UTI) [91, 92]
nasturtium and horseradish [93] have limited scientific evi-
dences. The sage herb is used as folk medicine in control-
ling UTI in Asia and Salvia Plebeia [94].
Lactobacillus sp. also reside in periurethrum, vagina and
bowel where it produces hydrogen peroxide, which assist
in retaining local pH and intercept the colonization of
uropathogens (like E. coli) [95–98]. But this concept needs
more through research to suggest the use of Lactobacillus
probiotics in prevention of UTI.
In Europe, an immunotherapeutics, OM-89 Uro Vaxom
and a sublingual bacterial vaccine, Iromune, both are com-
mercially available [99]. One of the most effective pre-
vention approaches is the designing of a potent vaccine.
OM-89 is prepared by lyophilization of the membrane pro-
teins of 18 different strains of uropathogenic E. coli. Its
safety and efficacy is verified and approved by the Euro-
pean Association of Urology. The ExPEC4V, a tetravalent
bioconjugate novel vaccine is under clinical trials. Further
controlled trials are needed to explore its potential [100].
Several other vaccines are also being developed and tested
for clinical efficacy [101, 102].
It is becoming quite difficult to eradicate the UTIs as
uropathogens are adapting to new environments and antibi-
otics day by day. Thus, there is need to find an alternate
pathway.
3. HERBAL MEDICINE FOR UTIs
Herbal medicine or medicinal plant is one of the popu-
lar complementary and alternative medicines (CAM) ther-
apies that involve the use of plants or plant extracts for
the therapeutic purpose [26]. As multidrug resistance is a
rapidly evolving process for bacteria and its high mutat-
ing power challenges all the anti-bacterial agents. So, here
comes the urgent need to discover more potent antibacte-
rial agents/compounds. Medicinal plants are good candi-
dates for this task as reported by several research groups
[27–30, 33–37] (Table I).
Traditional herbals have been used as a medical resource
in almost all cultures [30]. In developing countries, rural
people depend more on traditional medicine for various
diseases which also includes UTIs and STDs (Sexually
transmitted diseases). They go to these medicinal healers
(vaidyas, ojhas, etc.) for various reasons like being in the
same locality, lacking in advanced medical facilities, also
remedies given by these healers are cost-effective, eas-
ily affordable, quite safe with minimal or no side effects
[31, 32]. Thus, it becomes quite necessary to explore more
indigenous plants for their bioactive compounds.
Some researchers used volatile oils of common spices
like Ajwain (Trachyspermum copticum), cinnamon (Cin-
namomum zeylanicum), clove (Eugenia caryophyllus),
fennel (Foeniculum vulgare) and peppermint (Mentha pip-
perita) to check their antimicrobial activity against bacteria
isolated from the urine of UTI infected patients. They used
the agar well diffusion method and compared the zone
of inhibition of volatile oils with standard antibiotics like
gentamycin, norfloxacin, and ciprofloxacin. They noted the
greater antibacterial activity of Ajwain oil among all oth-
ers with the maximum value of zone of the inhibition of
46 mm against E. coli which was approximately 2.1 times
greater than the norfloxacin (22 mm) [30].
The antibacterial activity of leaf extract of Euphorbia
hirta, Erythrophleum suaveolens, and Thevetia peruviana
was checked against extended-spectrum beta-lactamase
(ESBL) producing bacteria (E. coli, Pseudomonas, Kleb-
siella, MRSA, Salmonella and Proteus) that cause UTI.
They used modified agar gel diffusion method and col-
lated their zone of inhibition where the methanolic extract
of T. peruviana exhibited the maximum zone of inhibition
against Klebsiella (15 mm), Proteus and E. coli (14 mm,
14 mm), MRSA (14 mm) and Pseudomonas (13 mm)
respectively [33].
The antibacterial activity of many other plants like
Coriander sativum, Syzygium aromaticum, Cinnamo-
mum cassia, Zingiber officinale, Terminalia chebula and
Azadirachta indica [34]; Solanum torvum [35]; Hemides
3500 J. Nanosci. Nanotechnol. 21, 3495–3512,2021
Devi et al. Herbal Medicine for Urinary Tract Infections with the Blazing Nanotechnology
musindicus, Malva sylvestris and Rubia cordifolia [36];
Glycyrrhiza glabra, Laurus nobilis and Brassica rapa [28];
Anogeissus acuminata, Bauhinia variegata, Boerhaavia
diffusa, Punica granatum, Soymida febrifuga, Terminalia
chebula, Tinospora cordifolia and Tribulus terrestris [29],
Tab l e I . Medicinal plants exhibiting anti-bacterial activity against UTIs.
Sr. no. Name of medicinal plant Nature of extract used Property Targeted microorganisms Results Reference
1Trachyspermum
copticum,
Cinnamomum
zeylanicum, Eugenia
caryophyllus,
Foeniculum vulgare,
and Mentha pipperita
Volatile oil Anti-bacterial Staphylococcus,
E. coli,
Proteus,
Shigella, and
Pseudomonas
T. copticum oil showed
greater anti-bacterial
activity among all oils
as the maximum value
of the zone of
inhibition 46 mm is
noted against
E. coli
[30]
2Euphorbia hirta and
Erythrophleum
suaveolens
Thevetia peruviana
Aqueous leaf
extract
Methanolic leaf
extract
Anti-bacterial ESBL E. coli,
Pseudomonas,
Klebsiella,
MRSA,
Salmonella and
Proteus
Among these, Methanolic
leaf extract of Thevetia
peruviana showed the
highest activity against
Klebsiella and ESBL
E. coli
[33]
3Agropyron repens L.
(rhizome part) and
Stigmata of Zea mays
L.
Betula spp.,
Orthosiphon stamineus
and Urtica spp. (leaves
of all 3)
Powdered plant
material
extracted with
ethanol: water
(1:1, v/v)
Anti-adhesive effects
under in-vitro
conditions against
the binding of
UPEC on the
bladder cell
surface.
Uropathogenic
Escherichia
coli
(UPEC)
Both decreased bacterial
adhesion by interacting
with bacterial O.M.
protein
All 3 showed
anti-adhesive effects
by interacting with
T24 bladder carcinoma
cells
Synergistic effects for
both extracts were also
showed the
anti-adhesive effect
[27]
4Coriander sativum,
Syzygium aromaticum,
Cinnamomum cassia,
Zingiber officinale,
Terminalia chebula
and Azadirachta indica
And their parts (leaves,
bark flower, rhizome,
and fruit)
Aqueous,
Ethanolic and
Methanolic
Anti-bacterial E. coli, Klebsiella
pneumoniae,
Pseudomonas
aeruginosa,
Enterobacter
faecalis and
Proteus
mirabilis
Among all extracts,
Ethanolic extract of
Cinnamomum cassia
showed the highest
antibacterial activity
on E. coli with DIZ of
21.33 ±0.57 mm
[34]
5 Fruits of Solanum torvum Aqueous Anti-bacterial E. coli,
Streptococcus,
Klebsiella
pneumoniae,
Entereococcus
and
Enterobacter
The best activity
observed At extract
conc. of 100 mg/ml in
Agar well diffusion
experiments
[35]
6Hemides musindicus,
Malva sylvestris and
Rubia cordifolia
Methanolic and
aqueous
extracts of the
dried stem in
the powdered
form
Anti-bacterial E. coli,
Pseudomonas,
Proteus,
Staphylococcus,
Klebsiella,
Serratia and
Alcaligenes
Methanolic extracts
showed more
antimicrobial potential
than aqueous extracts
of these herbs
[36]
7Syzygium aromaticum,
Glycyrrhiza glabra,
Laurus nobilis and
Brassica rapa
Methanolic Anti-bacterial E. coli,
Pseudomonas
aeruginosa, and
Acinetobacter
baumannii
S. aromaticum
was the most potent
plant against three
pathogens
[28]
were also tested against uropathogenic bacteria. The dif-
ferent solvents like water, ethanol, methanol, acetone,
etc. were utilized to prepare different plant extracts.
The ethanolic extract of Coriander sativum, Syzygium
aromaticum, Cinnamomum cassia, Zingiber officinale,
J. Nanosci. Nanotechnol. 21, 3495–3512, 2021 3501
Herbal Medicine for Urinary Tract Infections with the Blazing Nanotechnology Devi et al.
Tab l e I . Continued.
Sr. no. Name of medicinal plant Nature of extract used Property Targeted microorganisms Results Reference
8. Agropyron repens
(rhizome)
Aqueous,
Ethanolic,
Methanolic and
acetone based
extracts
Anti-adhesive activity
against bacterial
attachment to
human T24 bladder
cells
UPEC (Uropathogenic
E. coli)
Bioassay-guided
fractionation of
Acetone extract led to
identification
(E)-hexadecyl-3-(4-
hydroxyphenyl)-
acrylate (Hexadecyl
coumaric acid ester) 1,
which is responsible
for the anti-adhesive
activity
[37]
9Anogeissus acuminata,
Azadirachta indica,
Bauhinia variegata,
Boerhaavia diffusa,
Punica granatum,
Soymida febrifuga,
Terminalia chebula,
Tinospora cordifolia
and Tribulus terrestris
Methanolic
extract of dried
leaf samples
Anti-bacterial 2 Gram +ve bacteria
(Enterococcus faecalis
and Staphylococcus
aureus)and9Gram−ve
bacteria (Acinetobacter
baumannii, Citrobacter
freundii, Enterobacter
aerogenes, Escherichia
coli, Klebsiella oxytoca,
Klebsiella pneumonia,
Proteus mirabilis,
Proteus vulgaris,and
Pseudomonas
aeruginosa)
Three most effective
plants against
MDR-UTI Bacteria
in-vitro were
Anogeissus acuminata,
Punica granatum and
Soymida febrifuga
[29]
Notes: where O.M.—Outer membrane, ESBL—Extended spectrum beta-lactamase producing bacteria, MRSA—Methicillin-resistant Staphylococcus aureus, conc.—
Concentration, DIZ—Diameter of Inhibition zone, MDR—Multi-drug resistant.
Terminalia chebula, and Azadirachta indica reflected more
antibacterial activity than their aqueous and methanolic
extracts [34]. The aqueous extract of Solanum torvum
exhibited significant activity against Streptococcus spp.
and was found to be more pronounced than the control
ciprofloxacin, a standard drug employed as an antibiotic
during infection [35]. The methanolic extracts of Syzy-
gium aromaticum, Glycyrrhiza glabra, Laurus nobilis, and
Brassica rapa were tested against multi-drug resistant
bacteria E. coli, Pseudomonas aeruginosa, and Acineto-
bacter baumannii, and it was noted that S. aromaticum
was the most potent against the three pathogens [128].
The plants Anogeissus acuminata, Punica granatum,
and Soymida febrifuga are also effective against MDR
uropathogens [29].
The plant extracts can also show anti-adhesive activity
or declining bacterial adhesion to the bladder cells against
uropathogenic E. coli in various in vitro studies. The
extract of Agropyron repens L. (rhizome part) and plant
Stigmata of Zea mays declined the adhesion by interacting
with bacterial outer membrane protein while leaf extract
of Betula spp. Orthosiphon stamineus and Urtica spp.
showed anti-adhesive activity by interacting with T-24 cell
lines derived from human urinary bladder carcinoma [27].
In one study, a new compound Hexadecyl coumaric acid
ester from acetone extract of rhizome of Agropyron repens
L. was identified and it also showed anti-adhesive effect
against uropathogenic E. coli [37].
4. THE NANO APPROACH FOR DIAGNOSIS
AND TREATMENT OF UTIs
So many scientists around the globe are using nano-based
approaches in various fields like industries, energy storage,
pollution control, food sector, health sector, etc. Due to
their unique properties and applications, nano-sized parti-
cles have fascinated the entire world [68].
4.1. Nanoparticles and Nanocarriers
4.1.1. Properties
NPs are the materials having a size range from 1–100 nm
[103]. They have unique physical, chemical and biological
properties as compared to their bulk form. These unique
properties are due to their small size and high surface area,
intensified mechanical strength, higher reactivity or stabil-
ity during a reaction, etc. [104]. These can be of various
shapes, sizes and structures. Their surface can be irregular
or uniform [105].
Nanocarriers are the nanomaterials having sub-micron
particle size typically less than 500 nm [106, 107] and act
as colloidal drug delivery system [108]. These can be man-
ufactured from a variety of structures like lipids, proteins,
metals, inorganic and organometallic compounds, poly-
mers (synthetic and bio-polymers), etc. [109–112]. These
also have excellent biocompatibility, larger surface area,
versatility and better transfer controllability [113]. Tar-
geted therapy and bio-imaging could be enhanced by the
optomagnetic properties of these carriers. The different
3502 J. Nanosci. Nanotechnol. 21, 3495–3512,2021
Devi et al. Herbal Medicine for Urinary Tract Infections with the Blazing Nanotechnology
Table II. Nanoparticles and nanocarriers synthesized by chemical and physical approaches.
Techniques used UTI
Sr. NPs used in for characterization Size of Targeted methodology
no. the study of NPs NPs (nm) pathogens used Results Reference
1Al
2O3,
Fe3O4,
CeO2,
ZrO2,
and
MgO
TEM <50
9–11
<25
<100
<30
Pseudomonas
sp.,
Enterobacter
sp.,
Klebsiella sp.,
Escherichia
coli,
Proteus
morganii, and
Staphylococcus
Aureus
Well diffusion,
minimum
inhibitory
concentration
(MIC),
Minimum
bactericidal
concentration
(MBC) and
time killed
assay (only for
potential NPs)
All NPs showed
sensitivity
against all
pathogens
except
Pseudomonas
sp., Al2O3as
potential NP
showed
maximum
sensitivity of
(16.00 ±
0.21) mm and
5g/ml MIC
[69]
2ZnO UV-Vis,
SEM
HR-
TEM,
XRD,
SAED,
XPS
15 E. coli,
P. aeruginosa,
K. pneumonia
and
S. paucimobilis
Agar well
diffusion assay.
MIC, Time-kill
synergy assay
and bacterial
membrane
leakage assay
ZnO NPs +beta-
lactam
antibiotics
exhibit
enhanced
synergistic
biocidal
activity against
all isolated
potent clinical
ESBL
producers
[70]
3 AgNPs-hydrogel
composite
SEM,
TEM,
EDS,
and
XRD
8–14 Escherichia coli,
Pseudomonas
aeruginosa,
Klebsiella
pneumonia,
Staphylococcus
aureus and
P. mirabilis
Agar disc
diffusion
method
AgNPs-hydrogel
composite has
better
antibacterial
activity than
neat hydrogel
[71]
4 Silica-titania
sieves
UV-Vis,
FTIR
–E. coli- EC 2622,
E. coli 2739,
E. coli 2645,
E. coli 2749,
E. coli 2646,
E. coli 2732,
E. coli 2598
K. pneumonia
2727, K.
pneumonia–Kp
2633, K.
pneumonia
2770,
Morganella
morganii 2651,
P. mirabilis–
Pm 2648,
Enterococcus
fecalis–EF
2788,
Enterococcus
fecalis 2842
Agar disc
diffusion
method, MIC
The obtained
silica-titania
sieves loaded
with
isohidrafural
were found
most active
against
Klebsiella
pneumonia
(40 g/ml
average MIC),
deaminase
positive strain
(2.925 g/ml
average MIC)
and Proteus
mirabilis
(9.37 g/ml
average MIC).
[72]
J. Nanosci. Nanotechnol. 21, 3495–3512, 2021 3503
Herbal Medicine for Urinary Tract Infections with the Blazing Nanotechnology Devi et al.
Table II. Continued.
Techniques used UTI
Sr. NPs used in for characterization Size of Targeted methodology
no. the study of NPs NPs (nm) pathogens used Results Reference
5 Zn-doped CuO
NPs
DLS and
HR-TEM
20–95 E. coli AT C C
25922,
S. aureus
ATCC 29213
and P. mirabilis
In vitro flow
model for
biofilm
formation on a
catheter,
HET-CAM
irritation assay,
MTT assay,
mouse
splenocyte
assay, in vivo
experiment on
rabbit for
CAUTI and
histopathologi-
cal
examination
NPs coated
catheter showed
high antibiofilm
activity, low in
vitro
cytotoxicity,
negligible
associated
cytokine
secretion, and
absence of
detectable
irritation
[73]
6 Carbon-based
NPs—
Nanodiamonds
(NDs)
Raman
spectroscopy,
FTIR, TEM,
and Zeta
potential
analyzer
6 and 25 E. coli IH1128
(O75:K5: H−
strain)
–Dr adhesin
bearing
clinically
isolated
uropathogenic
strain,
The human
bladder
epithelial
carcinoma cell
line T24
Antibacterial
assay, Cell
viability assay,
TEM imaging
of T24 cells
treated with
NDs, Flow
cytometry,
Confocal
microscopy,
Bacterial
invasion assays,
Statistical
analyses
(ANOVA)
6 nm NDs
showed lower
cytotoxicity
and better
ability to kill
extracellular
and
intracellular
bacteria
[74]
medical applications require different types of nanocarriers
and these can also be modified as the need changes [114].
4.1.2. Synthesis
Various kinds of nanoparticles (NPs) have been synthe-
sized for the treatment of several ailments including UTIs
by different chemical and physical methods (Table II), and
biological or biogenic methods (Table III) using ‘top to
bottom’ or ‘bottom to up’ approaches. The top to bottom
is a destructive approach where bulk material is broken
down into NPs by using physical methods like laser abla-
tion, mechanical milling, sputtering, grinding, etc. [115].
The bottom to up approach is a constructive approach
where assembling of atoms to clusters/nuclei lead to for-
mation of NPs. It involves chemical methods like sol–gel,
pyrolysis, chemical vapour deposition, etc. and biological
methods involving plants, bacteria, fungi, etc. [116]. To
strengthen the quality and lower the manufacturing costs,
various synthesis methodologies have either been devel-
oped or improved [117].
The major drawbacks associated with physicochemical
methods are high temperature or pressure, use of toxic
chemicals, production of toxic by-products, higher rates of
contamination due to use of chemicals and cost. While bio-
genic methods are environment-friendly, sustainable and
non-toxic. Among these green route or plant based synthe-
sis offers more advantages like free of contamination, more
stability, inexpensiveness, excellent antimicrobial and anti-
fungal properties, etc. [118].
Various instruments like UV–Vis, DLS, XRD, FTIR,
Vis-NIR, HR-TEM, TEM, SEM, SEM-EDX, SAED,
AFM, NTA, EDAX, and TGA are being used for their
characterization [69–81].
4.2. Potential of Nanoparticles and Nanocarriers
Against Uropathogens
In several studies, uropathogens were isolated from the
urine of patients. Then the synthesized NPs were tested
against pathogenic cultures. They resulted in a very good
zone of inhibition, indicating the good biomedical capabil-
ity of synthesized NPs [69, 74, 79]. Several types of NPs
like Al2O3,Fe
3O4,CeO
2,ZrO
2,MgO,ZnO,CuO,AgNPs,
etc. have been synthesized using chemical and physical
approaches and targeted against various uropathogens [69–
74]. Nanocarriers like ZnO [70], AgNPs-hydrogel [71],
silica-titania sieves [73], Nano-diamonds (Carbon-based
3504 J. Nanosci. Nanotechnol. 21, 3495–3512,2021
Devi et al. Herbal Medicine for Urinary Tract Infections with the Blazing Nanotechnology
Table III. Nanoparticles synthesized by the biogenic approach.
The technique
used for Targeted
Sr. Name of Part NPs used in characterization Size UTI
no. organism used the study of NPs obtained (nm) pathogens Results Reference
1Bacillus sp.
(isolated from
seaweed)
Whole bacteria Ag UV-vis, XRD,
FTIR, EDAX,
AFM, and
TEM
10–30 Escherichia
coli, Pseu-
domonas
aeruginosa,
Klebsiella
sp., Proteus
mirabilis
and
Serratia
marcescens
E. coli was
found
highly
sensitive
with a zone
diameter of
13±23 mm
at conc. of
15 g/ml
[75]
2Nigella sativa
(plant extract)
Seeds Ag UV-vis, XRD,
FTIR, EDAX,
and SEM
1.5–4 E. coli and
S. aureus
Inhibit the
pathogens
[76]
3Lactobacillus
crispatus
Whole bacteria Ti AFM 70.98 E. coli,
S. aureus,
Klebsiella
pneumonia,
Morganella
morganii
and Acine-
tobacter
baumani
NPs had
antibacte-
rial,
anti-
biofilm,
anti-
adhesive,
urease and
hemolysis
activity
inhibitor
properties
against
E. coli,
S. aureus,
Klebsiella
pneumonia
and Acine-
tobacter
baumani
[77]
4Tabernaemontana
divaricate
leaves CuO UV-Vis
absorption
spectroscopy,
XRD, FT-IR,
SEM with
EDX and TEM
48 ±4Escherichia
coli
Highest zone
of
inhibition
was
observed
with a zone
diameter of
17 ±1mm
at conc. of
25 g/ml
[78]
5Passiflora
caerulea
leaves ZnO UV-Vis
spectroscopy,
XRD, FT-IR,
SEM, EDAX,
and AFM
30–50 Klebsiella
pneumonia,
Enterococ-
cus sp.,
Escherichia
coli
and
Streptococcus
sp.
Maximum
zone
of
inhibition
observed in
E. coli.
(gram −ve)
and
the
minimum
in Entero-
coccus sp
(gram +ve)
[79]
J. Nanosci. Nanotechnol. 21, 3495–3512, 2021 3505
Herbal Medicine for Urinary Tract Infections with the Blazing Nanotechnology Devi et al.
Table III. Continued.
The technique
used for Targeted
Sr. Name of Part NPs used in Characterization Size UTI
no. organism used the study of NPs Obtained (nm) pathogens Results Reference
6Catharanthus
roseus
leaf S NTA, TEM,
Zetasizer,
XRD, and
FTIR
20–86 E. coli,
S. aureus,
Klebsiella
pneumonia,
Pseudomonas
aeruginosa,
P. mirabilis
and
E. fecalis
SNPs were
effective
against
pathogens.
Combina-
tion of
antibiotics
(AMX, TR,
NX) with
SNPs
shows the
synergistic
effect on
bacteria
[80]
7Alcaligenes sp.
(coral-
associated
bacteria)
Whole bacteria Ag UV-vis, XRD,
FTIR, AFM,
SEM, and TEM
30–50 Bacillus sp.,
E. coli,
C. albicans,
K. pneumo-
nia,
P. aerugi-
nosa and
S. aureus
The MIC dose
of 30 g/ml
of AgNPs
showed a
significant
effect on
antimicro-
bial and
biofilm
formation.
[81]
Notes: Where High resolution transmittance electron microscopy (HR-TEM), selective area electron diffraction (SAED), X-ray photoelectron spectroscopy (XPS), NTA
(Nanoparticle tracking analysis), EDAX (Energy dispersive analysis of X-ray), carboxymethyl cellulose (CMC), polyvinyl alcohol (PVA), ethylene glycol diglycidyl ether
(EGDE), Cefotaxime(CF), Ampicillin (A), Ceftriaxone (CI), Cefepime (CPM), AMX (Amoxicillin), XRD—X-ray diffraction, FTIR—Fourier transform infrared spectroscopy,
SEM—Scanning electron microscopy, EDX—Energy dispersive X-ray analysis OR EDAX—Energy dispersive analysis of X-ray, TEM—Transmission electron microscopy,
AFM—Atomic force microscopy.
NPs, NDs) [74], etc. have also been used as the drug deliv-
ery systems and all of these exhibited better anti-bacterial
activities in comparison to the NPs or antibiotics alone
(Fig. 5).
The commercially prepared metal oxide NPs of Al2O3,
Fe3O4,CeO
2,ZrO
2, and MgO were employed against UTI
pathogens Pseudomonas sp., Enterobacter sp., Klebsiella
Figure 5. Different kinds of NPs synthesized by various approaches.
sp., Escherichia coli, Proteus morganii, and Staphylococ-
cus aureus, to check potential antimicrobial activity. All
NPs showed sensitivity against all pathogens except Pseu-
domonas sp. Among these, the Al2O3NPs showed maxi-
mum sensitivity of (16.00±0.21) mm against E. coli at
5g/ml MIC [69].
The Low-temperature sol–gel method was used for the
synthesis of ZnO NPs and the antimicrobial potency of
ZnO NPs alone and in combination with four -lactam
antibiotics, cefotaxime (CF), ampicillin (A), ceftriaxone
(CI) and cefepime (CPM), was analyzed against ESBL
producers (E. coli, P. aeruginosa, K. pneumonia, and
S. paucimobilis). All these bacteria have been proved resis-
tant to these antibiotics. The zone of inhibition, ZOI (mm)
of ZnO NPs for E. coli, K. pneumonia, S. paucimobilis,
and P. aeruginosa were 10 ±0.66, 12 ±0.00, 11.33 ±
1.10 and 0.7 ±0.66 respectively. While, the ZOI (mm)
of ZnO NPs +antibiotics against ESBL were ZnO NPs +
CF-13, ZnO NPs +A-12, ZnO NPs +CI-9, ZnO NPs +
CPM-10 (for E. coli), ZnO NPs +CF-7, ZnO NPs +A-5,
ZnO NPs +CI-7, ZnO NPs +CPM-14 (for K. pneumo-
nia), ZnO NPs +CF-10, ZnO NPs +A-6, ZnO NPs +
CI-8, ZnO NPs +CPM-11 (for S. paucimobilis)and
ZnO NPs +CF-12, ZnO NPs +A-10, ZnO NPs +CI-11,
3506 J. Nanosci. Nanotechnol. 21, 3495–3512,2021
Devi et al. Herbal Medicine for Urinary Tract Infections with the Blazing Nanotechnology
ZnO NPs +CPM-8 (for P. aeruginosa). The ZnO NPs +
antibiotics exhibited enhanced synergistic biocidal activ-
ity and enhanced membrane permeability by leakage of
reducing sugar [70].
In one study, AgNPs-hydrogel composites were pre-
pared and targeted against UTI pathogens (Escherichia
coli, Pseudomonas aeruginosa, Klebsiella pneumonia,
Staphylococcus aureus, and P. mirabilis). The hydrogel
was synthesized using carboxymethyl cellulose (CMC),
polyvinyl alcohol (PVA), ethylene glycol diglycidy ether
(EGDE) and AgNPs were incorporated in hydrogel by
microwave radiation. Then the comparison of the antibac-
terial activity of neat hydrogel, AgNPs-hydrogel compos-
ite, and standard drug Kanamycin was performed using
disc diffusion method. The AgNPs-hydrogel composites
showed better bactericidal activity as compared to neat
hydrogel but almost similar to kanamycin. It was observed
that the antibacterial activity was directly proportional
to the concentration of both neat hydrogel and AgNPs-
hydrogel composite. The zone of inhibition was 16.6 mm
at a concentration of 5 mg/ml of AgNPs-hydrogel com-
posite in the case of E. coli. [71].
The nanostructured silica-titania sieves were prepared
and loaded with drug isohidrafural. These loaded sieves
were found to be the most active against Klebsiella
pneumonia (40 g/ml average MIC), deaminase positive
strain (2.925 g/ml average MIC) and Proteus mirabilis
(9.37 g/ml average MIC) while the unloaded sieves
revealed the highest antimicrobial activity against gram-
positive cocci. [72, 86]. In a catheter-associated UTI study,
the Zn-doped CuO NPs were used to coat the urinary
catheter with the help of ultrasound nanofabrication. The
size of the NPs was 35–95 nm on the internal side and
20–75 nm on the external side of the catheter. These
Zn-doped CuO NPs coated catheter exhibited the high
antibiofilm activity, low in vitro cytotoxicity, negligible
cytokine secretion and no sign of irritation [73].
The nanodiamonds (NDs) are biocompatible nanomate-
rials that can be used for targeted therapeutic applications.
In one research, the NDs were used against uropathogenic
E. coli (UPEC) and human bladder epithelial carcinoma
cell line, T24. The NDs of 6 nm size showed lower cyto-
toxicity and better ability to kill extracellular and intracel-
lular bacteria [74].
The biogenic synthesis of NPs involves the use of
plant and microbes. In various studies, the plants and
bacteria have been utilized for the synthesis of NPs to
analyze the antimicrobial activity against UTI pathogens.
The plants like Tabernaemontana divaricate, Passiflora
caerulea, Nigella sativa,andCatharanthus roseus, were
used in green synthesis of CuO, ZnO, Ag and S NPs,
respectively [75, 76, 78–81] while the Bacillus sp.and
Alcaligenes sp. are used in the synthesis of AgNPs [75, 81]
while Lactobacillus crispatus is used in titanium NPs [77].
The Bacillus sp., isolated from seaweed Padina gym-
nosphora was used to synthesize silver NPs. The disc
diffusion assay, CFU assay, and MIC test revealed that
the conc. of more than 10 g/ml of silver NPs inhib-
ited the growth of UTI pathogens and at the conc.
of 15 g/ml, the diameter of the zone of inhibition
was 13 ±23 mm against E. coli. [75]. On the other
hand, the Ag NPs synthesized using seed extract of
Nigella sativa showed a zone of inhibition of 10 mm
and 12 mm against E. coli and S. aureus respec-
tively [76]. The TiO2NP synthesized using bacteria
showed antibacterial, anti-biofilm, antiadhesive, urease
and hemolysis activity against E. coli, S. aureus, Kleb-
siella pneumonia, Morganella morganii,andAcineto-
bacter baumani. The significant reduction in biofilm
formation, hemolysin and urease production was observed
at 16 mg/ml conc. while at 32 mg/ml conc., the inhibitory
effect against recurrent UTI causing bacteria was
reported [77].
The green synthesis of various NPs has been done using
leaf extracts and targeted against different UTI pathogens.
The CuO NPs were synthesized using leaf extract of
Tabernaemontana divaricate and the antimicrobial activity
was tested against E. coli. The highest zone of inhibition
was observed with a zone diameter of 17±1 mm at conc.
of 25 g/ml, which was more than the positive control
(i.e., 7 ±0.56 mm zone of inhibition) [78]. The ZnO NPs
were synthesized using leaf extract of Passiflora caerulea
and used against Klebsiella pneumonia, Enterococcus sp.,
Escherichia coli and Streptococcus sp. (UTI pathogens).
It was observed that NPs showed antibacterial activity in a
dose-dependent manner. The Maximum zone of Inhibition
observed in E. coli. (gram −ve) and minimum in Entero-
coccus spp. (gram +ve) [79].
The Catharanthus roseus leaf extract was employed to
synthesize sulfur nanoparticles (SNP) by co-precipitation
method. These polydispersed NPs were used to check
potential antibacterial activity in combination with antibi-
otics particularly amoxicillin and trimethoprim against
E. coli, S. aureus, Klebsiella pneumonia, Pseudomonas
aeruginosa, P. mirabilis,andE. fecalis. The maximum
inhibition zone of 14.66 mm was observed for SNPs +
AMX (Amoxicillin). The SNPs along with antibiotics
showed the synergistic effect on bacteria [80]. A coral-
associated bacterium, Alcaligenes sp. was utilized for the
preparation of AgNPs. These NPs were also employed to
the coating of the catheter. The MIC dose of 30 g/ml
of AgNPs showed a significant effect on antimicrobial
and biofilm formation. The greater zone of inhibition
(25 mm at conc. of 40 g/ml) was observed against
P. aeruginosa [81].
4.3. Advantages and Limitations of NPs During
Drug Delivery
NPs can be used as drug delivery systems because they
can efficiently transport through fine capillary blood ves-
sels, lymphatic endothelium, urothelium and umbrella cells
J. Nanosci. Nanotechnol. 21, 3495–3512, 2021 3507
Herbal Medicine for Urinary Tract Infections with the Blazing Nanotechnology Devi et al.
of bladder permeability barrier, etc. [119]. They have a
higher binding capacity to certain biomolecules, longer
blood concentration and circulation-duration, better accu-
mulation in target tissues and reduced immune response
and oxidative stress in tissues [82–84]. These materi-
als also provide an increase in aqueous solubility of the
drug, protect the drug from degradation, increase bioavail-
ability, targeted drug delivery, prolonged release of the
drug, decrease toxic side effects and allow rapid for-
mulation development [85]. Therefore, these are benefi-
cial over the conventional medicines as exhibit superior
efficacy, safety, physicochemical properties and pharma-
cokinetics/pharmacodynamics profiles of pharmaceutical
ingredients [82].
There are some challenges associated with nanotechnol-
ogy based drug delivery systems like the toxicity of NPs
on cell, tissue or organ system [119–122], development of
multifunctional and optimized drug delivery [123], dosage
fixation of NPs for in vitro experiments [124, 125], scaling
up of the processing of therapeutics to reach rapidly to the
market [126], etc.
5. CONVENTIONAL ANTIBIOTICS VERSUS
NANO-ANTIBIOTICS
NPs or Nanomaterials revealing antimicrobial properties
by themselves or enhancing the effectiveness of antibiotic
administration are called as Nano-antibiotics [127]. Sev-
eral types of nano-antibiotics or nano drug delivery vehi-
cles have been manufactured over the past years for this
purpose. Conventional drugs or antibiotics lack specificity
[128] and their penetration for the target cell or tissue
whereas polymeric NPs themselves [129] or surface mod-
ified NPs could deliver the drug efficiently to the special
targeted tissue [130]. Nano-antibiotics offer high thera-
peutic index, composed drug release, prolonged half-life
of drug circulation, and enhanced pharmacokinetics [121],
whereas conventional therapies are correlated with inter-
rupted native microflora [131, 132] and tedious detection
techniques also.
6. CONCLUSION
Urinary tract infection is becoming a serious infection day
by day as the causal organism bacteria are becoming more
and more resistant to antibiotics. Thus, there is increasing
pressure on the healthcare sector to develop more potent
drugs. Extracts of phytoconstituents have all the essential
and novel compounds which can help out. This review pre-
sented an overview of various herbal medicines and their
effectiveness against uropathogens, and to enhance this
efficacy by the use of Nanotechnology. Several types of
metallic NPs (Al2O3,Fe
3O4, ZnO, CuO, AgNPs), AgNPs-
hydrogel composites, carbon-based NPs (nano-diamonds,
NDs), nanostructured silica-titania sieves, etc. have been
prepared and targeted against various uropathogens. Phy-
tochemicals based green synthesis offer more capable NPs
with higher bioactivity. The integration of nanotechnology
with the available and advanced diagnostic methods may
overcome several difficulties faced today. But still, there
is a need for more research in this area to get better and
more promising results.
Acknowledgment: The authors are grateful to Dr. Anuj
Nehra, Centre for Bio-Nanotechnology, Chaudhary Charan
Singh Haryana Agricultural University, Hisar for critically
going through the manuscript.
References and Notes
1. Gupta, K., Grigoryan, L. and Trautner, B., 2017. Urinary tract
infection. Annals of Internal Medicine, 167(7), pp.ITC49–ITC64.
2. Kebira, A.N., Ochola, P. and Khamadi, S., 2009. Isolation and
antimicrobial susceptibility testing of Escherichia coli causing uri-
nary tract infections. Journal of Applied Biosciences,22, pp.1320–
1325.
3. Stamm, W.E. and Norrby, S.R., 2001. Urinary tract infections:
disease panorama and challenges. The Journal of Infectious Dis-
eases,183(Supplement_1), pp.S1–S4.
4. Foxman, B., 2014. Urinary tract infection syndromes: Occurrence,
recurrence, bacteriology, risk factors, and disease burden. Infectious
disease clinics of North America,28(1), pp.1–13.
5. Hootan, T.M., 2003.Urinary Tract Infection in Adults, 2nd edn,
Johnson, R.J. and Feehally, J., (Eds). Comprehensive Clinical
Nephrology, Mosby, London, pp.731–744.
6. Hooton, T.M., 2012. Uncomplicated urinary tract infection. New
England Journal of Medicine,366(11), pp.1028–1037.
7. Nielubowicz, G.R. and Mobley, H.L., 2010. Host—Pathogen inter-
actions in urinary tract infection. Nature Reviews Urology,7(8),
pp.430–441.
8. Foxman, B., 2010. The epidemiology of urinary tract infection.
Nature Reviews Urology,7, pp.653–660.
9. Lichtenberger, M. and Hooton, T.M., 2008. Complicated uri-
nary tract infections. Current Infectious Disease Reports,10,
pp.405–505.
10. Levison, M.E. and Kaye, D., 2013. Treatment of complicated uri-
nary tract infections with an emphasis on drug-resistant gram-
negative uropathogens. Current Infectious Disease Reports,15(2),
pp.109–115.
11. Lo, E., Nicolle, L.E., Coffin, S.E., Gould, C., Maragakis, L.L.,
Meddings, J., Pegues, D.A., Pettis, A.M., Saint, S. and Yokoe,
D.S., 2014.Strategies to prevent catheter-associated urinary tract
infections in acute care hospitals: 2014 update. Infection Control &
Hospital Epidemiology,35(5), pp.464–479.
12. Chenoweth, C.E., Gould, C.V. and Saint, S., 2014. Diagnosis, man-
agement, and prevention of catheter-associated urinary tract infec-
tions. Infectious Disease Clinics of North America, 28, pp.105–119.
13. Buonanno, A.P. and Damweber, B.J., 2006. Review of urinary tract
infection. U.S. Pharmacist,31(6), pp.26–36.
14. Hooton, T.M., Scholes, D., Stapleton, A.E., Roberts, P.L.,
Winter, C., Gupta, K., Samadpour, M. and Stamm, W.E., 2000.
A prospective study of asymptomatic bacteriuria in sexually
active young women. New England Journal of Medicine,343(14),
pp.992–997.
15. Raz, R., 2003. Asymptomatic bacteriuria: Clinical significance and
management. International Journal of Antimicrobial Agents,22,
pp.45–47.
16. Centers for Disease Control and Prevention, U.S. Department of
Health & Human Services, USA (https://www.cdc.gov/antibiotic-
use/community/for-patients/common-illnesses/uti.html) last
updated on April 17, 2015.
3508 J. Nanosci. Nanotechnol. 21, 3495–3512,2021
Devi et al. Herbal Medicine for Urinary Tract Infections with the Blazing Nanotechnology
17. Gupta, K., Hooton, T.M., Naber, K.G., Wullt, B., Colgan, R.,
Miller, L.G., Moran, G.J., Nicolle, L.E., Raz, R., Schaeffer, A.J.
and Soper, D.E., 2011. International clinical practice guidelines for
the treatment of acute uncomplicated cystitis and pyelonephritis
in women: A 2010 update by the Infectious Diseases Society of
America and the European Society for Microbiology and Infectious
Diseases. Clinical Infectious Diseases, 52(5), pp.e103–e120.
18. Zhanel, G.G., Hisanaga, T.L., Laing, N.M., DeCorby, M.R., Nichol,
K.A., Palatnick, L.P., Johnson, J., Noreddin, A., Harding, G.K.,
Nicolle, L.E. and Hoban, D.J., 2005. Antibiotic resistance in out-
patient urinary isolates: Final results from the North American
urinary tract infection collaborative alliance (NAUTICA). Interna-
tional Journal of Antimicrobial Agents, 26(5), pp.380–388.
19. Swami, S.K., Liesinger, J.T., Shah, N., Baddour, L.M. and
Banerjee, R., 2012. Incidence of Antibiotic-Resistant Escherichia
coli Bacteriuria According to Age and Location of Onset:
A Population-Based Study from Olmsted County, Minnesota.
In Mayo Clinic Proceedings, August; Elsevier. Vol. 87, pp.753–759.
20. FDA. Drug safety communication: FDA ad-vises restricting fluoro-
quinolone antibiotic use for certain uncomplicated infections; warns
about disabling side effects that can occur together. Available at:
http://www.fda.gov/Drugs/DrugSafety/ucm500143.htm. Accessed
May 26, 2016.
21. Manikandan, S., Ganesapandian, S., Singh, M. and Kumaraguru,
A.K., 2011. Emerging of multidrug resistance human pathogens
from urinary tract infections. Current Research in Bacteriol-
ogy, 4(1), pp.9–15.
22. Tamalli, M., Bioprabhu, S. and Alghazal, M.A., 2013. Urinary tract
infection during pregnancy at Al-khoms, Libya. International Jour-
nal of Medicine and Medical Sciences, 3(5), pp.455–459.
23. Venkatesh, R.K., Prabhu, M.M., Nandakumar, K. and RPai, K.S.,
2016. Urinary tract infection treatment pattern of elderly patients
in a tertiary hospital setup in South India: A prospective study.
Journal of Young Pharmacists, 8(2), pp.108–113.
24. Crider, K.S., Cleves, M.A., Reefhuis, J., Berry, R.J., Hobbs, C.A.
and Hu, D.J., 2009. Antibacterial medication use during preg-
nancy and risk of birth defects: National birth defects preven-
tion study. Archives of Pediatrics & Adolescent Medicine, 163(11),
pp.978–985.
25. Ailes, E.C., Gilboa, S.M., Gill, S.K., Broussard, C.S., Crider, K.S.,
Berry, R.J., Carter, T.C., Hobbs, C.A., Interrante, J.D., Reefhuis, J.
and National Birth Defects Prevention Study, 2016. Association
between antibiotic use among pregnant women with urinary tract
infections in the first trimester and birth defects, National Birth
Defects Prevention Study 1997 to 2011. Birth Defects Research
Part A: Clinical and Molecular Teratology, 106(11), pp.940–949.
26. World Health Organization, 2004. WHO guidelines on
developing consumer information on proper use of
traditional, complementary and alternative medicine,
https://apps.who.int/iris/handle/10665/42957.
27. Rafsanjany, N., Lechtenberg, M., Petereit, F. and Hensel, A.,
2013. Antiadhesion as a functional concept for protection against
uropathogenic Escherichia coli:In vitro studies with tradition-
ally used plants with antiadhesive activity against uropathog-
nic Escherichia coli.Journal of Ethnopharmacology,145(2),
pp.591–597.
28. Aziz, M.A., Adnan, M., Rahman, H. and Fathi, E.L.S.A.Y.E.D.,
2017. Antibacterial activities of medicinal plants against multidrug
resistant urinary tract pathogens. Pakistan Journal of Botany,49(3),
pp.1185–1192.
29. Mishra, M.P., Rath, S., Swain, S.S., Ghosh, G., Das, D. and Padhy,
R.N., 2017.In vitro antibacterial activity of crude extracts of nine
selected medicinal plants against UTI causing MDR bacteria. Jour-
nal of King Saud University-Science,29(1), pp.84–95.
30. Kumar, A., Jhadwal, N., Lal, M. and Singh, M., 2012. Antibac-
terial activity of some medicinal plants used against UTI caus-
ing pathogens. International Journal of Drug Development and
Research,4, pp.278–283.
31. Prachi,N.,Kumar,D.andKasana,M.S.,2009. Medicinal plants of
Muzaffarnagar district used in treatment of urinary tract and kidney
stones. Indian Journal of Traditional Knowledge,8(2), pp.191–195.
32. Hossan, S., Agarwala, B., Sarwar, S., Karim, M., Jahan, R. and
Rahmatullah, M., 2010. Traditional use of medicinal plants in
Bangladesh to treat urinary tract infections and sexually transmitted
diseases. Ethnobotany Research and Applications,8, pp.61–74.
33. Singh, V., Jaryal, M., Gupta, J. and Kumar, P., 2012. Antibacterial
activity of medicinal plants against extended spectrum beta lacta-
mase producing bacteria causing urinary tract infection. Interna-
tional Journal of Drug Research and Technology,2(3), pp.263–267.
34. Tabassum, H., Ali, M.N., Al-Jameil, N. and Khan, F.A., 2013.Eval-
uation of antibacterial potential of selected plant extracts on bacte-
rial pathogens isolated from urinary tract infections. International
Journal of Current Microbiology and Applied Sciences, 2(10),
pp.353–368.
35. Begam, A.K.U. and Senthilkumar, R., 2014. Antibacterial activity
of a traditional medicinal plant against pathogenic microorganisms
causing urinary tract infection. World Journal of Pharmacy and
Pharmaceutical Sciences,3(7), pp.1116–1126.
36. Rawat, S. and Swarup, S., 2015. Antimicrobial activity of
Ayurvedic herbs against urinary tract infection pathogens. Journal
of Chemical and Pharmaceutical Research,7(4), pp.1461–1465.
37. Beydokthi, S.S., Sendker, J., Brandt, S. and Hensel, A., 2017.Tra-
ditionally used medicinal plants against uncomplicated urinary tract
infections: Hexadecyl coumaric acid ester from the rhizomes of
Agropyron repens (L.) P. Beauv. with antiadhesive activity against
uropathogenic E. coli. Fitoterapia, 117, pp.22–27.
38. Rangaiahagari, A., Nyirabanzi, J., Uwizeyimana, J.P., Ngoga, E.
and Wane, J., 2015. Comparison of urine culture and urine dipstick
nitrite test in diagnosis of urinary tract infection. Rwanda Medical
Journal, 72(1), pp.5–7.
39. Pezzlo, M., 2014. Laboratory diagnosis of urinary tract infec-
tions: Guidelines, challenges, and innovations. Clinical Microbiol-
ogy Newsletter, 36(12), pp.87–93.
40. Fritzenwanker, M., Imirzalioglu, C., Chakraborty, T. and
Florian, M., 2016. Modern diagnostic methods for urinary tract
infections. Expert Review of Anti-Infective Therapy, 14(11),
pp.1047–1063.
41. Kupelian, A.S., Horsley, H., Khasriya R, Amussah, R.T.,
Badiani, R., Courtney, A.M., Chandhyoke, S.N., Riaz, U.,
Savlani, K., Moledina, M., Montes, S., O’Connor, D., Visavadia, R.,
Kelsey, M., Rohn, J. and Malone-Lee, J.L., 2013. Discrediting
microscopic pyuria and leucocyte esterase as diagnostic surrogates
for infection in patients with lower urinary tract symptoms: Results
from a clinical and laboratory evaluation. BJU Int., 112(2), pp.231–
238.
42. Ferry, S.A., Holm, S.E., Ferry, B.M. and Monsen, T.J., 2015.
High diagnostic accuracy of nitrite test paired with urine sediment
can reduce unnecessary antibiotic therapy. The Open Microbiology
Journal, 9, pp.150–159.
43. Falbo, R., Sala, M.R., Signorelli, S., Venturi, N., Signorini, S. and
Brambilla, P., 2012. Bacteriuria screening by automated whole-
field-image-based microscopy reduces the number of necessary
urine cultures. Journal of Clinical Microbiology, 50(4), pp.1427–
1429.
44. Tessari, A., Osti, N. and Scarin, M., 2015. Screening of pre-
sumptive urinary tract infections by the automated urine sediment
analyser sediMAX. Clinical Chemistry and Laboratory Medicine
(CCLM), 53(s2), pp.s1503–s1508.
45. Schmiemann, G., Kniehl, E., Gebhardt, K., Matejczyk, M.M.
and Hummers-Pradier, E., 2010.The diagnosis of urinary tract
J. Nanosci. Nanotechnol. 21, 3495–3512, 2021 3509
Herbal Medicine for Urinary Tract Infections with the Blazing Nanotechnology Devi et al.
infection: A systematic review. Deutsches Ärzteblatt Interna-
tional, 107(21), pp.361–367.
46. Wilson, M.L. and Gaido, L., 2004. Laboratory diagnosis of urinary
tract infections in adult patients. Clinical Infectious Diseases, 38(8),
pp.1150–1158.
47. Kumar, M.S. and Das, A.P., 2017. Emerging nanotechnology based
strategies for diagnosis and therapeutics of urinary tract infec-
tions: A review. Advances in Colloid and Interface Science, 249,
pp.53–65.
48. Bonkat, G., Wernli, L., Braissant, O., Rieken, M., Müller, G.,
Wyler, S., Gasser, T. and Bachmann, A., 2013. 618 Growth quantifi-
cation and rapid drug susceptibility testing of uropathogenic Can-
dida albicans by isothermal microcalorimetry. European Urology
Supplements, 12(1), p.e618.
49. Braissant, O., Bachmann, A. and Bonkat, G., 2015. Microcalori-
metric assays for measuring cell growth and metabolic activity:
Methodology and applications. Methods, 76, pp.27–34.
50. Das, A.P., Kumar, P.S. and Swain, S., 2014. Recent advances in
biosensor based endotoxin detection. Biosensors and Bioelectron-
ics, 51, pp.62–75.
51. Barnes, L., Heithoff, D.M., Mahan, S.P., Fox, G.N., Zambrano, A.,
Choe, J., Fitzgibbons, L.N., Marth, J.D., Fried, J.C., Soh, H.T. and
Mahan, M.J., 2018. Smartphone-based pathogen diagnosis in uri-
nary sepsis patients. EBioMedicine, 36, pp.73–82.
52. Kim, Y., Park, K.G., Lee, K. and Park, Y.J., 2015. Direct iden-
tification of urinary tract pathogens from urine samples using
the Vitek MS system based on matrix-assisted laser desorption
ionization-time of flight mass spectrometry. Annals of Laboratory
Medicine, 35(4), pp.416–422.
53. Chaki, N.K. and Vijayamohanan, K., 2002. Self-assembled mono-
layers as a tunable platform for biosensor applications. Biosensors
and Bioelectronics, 17(1–2), pp.1–12.
54. Pan, Y., Sonn, G.A., Sin, M.L., Mach, K.E., Shih, M.C., Gau, V.,
Wong, P.K. and Liao, J.C., 2010. Electrochemical immunosensor
detection of urinary lactoferrin in clinical samples for urinary tract
infection diagnosis. Biosensors and Bioelectronics, 26(2), pp.649–
654.
55. Mach, K.E., Du, C.B., Phull, H., Haake, D.A., Shih, M.C., Baron,
E.J. and Liao, J.C., 2009. Multiplex pathogen identification for
polymicrobial urinary tract infections using biosensor technology:
A prospective clinical study. The Journal of Urology, 182(6),
pp.2735–2741.
56. Mach, K.E., Mohan, R., Baron, E.J., Shih, M.C., Gau, V., Wong,
P.K. and L i a o , J .C . , 2011. A biosensor platform for rapid antimi-
crobial susceptibility testing directly from clinical samples. The
Journal of Urology, 185(1), pp.148–153.
57. Heytens, S., De Sutter, A., Coorevits, L., Cools, P., Boelens, J.,
Van Simaey, L., Christiaens, T., Vaneechoutte, M. and Claeys, G.,
2017. Women with symptoms of a urinary tract infection but a neg-
ative urine culture: PCR-based quantification of Escherichia coli
suggests infection in most cases. Clinical Microbiology and Infec-
tion, 23(9), pp.647–652.
58. Fouts, D.E., Pieper, R., Szpakowski, S., Pohl, H., Knoblach, S.,
Suh, M.J., Huang, S.T., Ljungberg, I., Sprague, B.M., Lucas, S.K.
and Torralba, M., 2012. Integrated next-generation sequencing of
16S rDNA and metaproteomics differentiate the healthy urine
microbiome from asymptomatic bacteriuria in neuropathic blad-
der associated with spinal cord injury. Journal of Translational
Medicine, 10(1), pp.174–190.
59. Whitesides, G.M., 2006. The origins and the future of microfluidics.
Nature, 442(7101), pp.368–373.
60. Zhang, Y., Shin, D.J. and Wang, T.H., 2013. Serial dilution via
surface energy trap-assisted magnetic droplet manipulation. Lab on
a Chip, 13(24), pp.4827–4831.
61. Li,B.,Yu,Q.andDuan,Y.,2015. Fluorescent labels in biosensors
for pathogen detection. Critical Reviews in Biotechnology, 35(1),
pp.82–93.
62. Leung, K., Zahn, H., Leaver, T., Konwar, K.M., Hanson, N.W.,
Pagé, A.P., Lo, C.C., Chain, P.S., Hallam, S.J. and Hansen, C.L.,
2012. A programmable droplet-based microfluidic device applied to
multiparameter analysis of single microbes and microbial commu-
nities. Proceedings of the National Academy of Sciences, 109(20),
pp.7665–7670.
63. Davenport, M., Mach, K.E., Shortliffe, L.M.D., Banaei, N., Wang,
T.H . and Li ao, J . C., 2017. New and developing diagnostic technolo-
gies for urinary tract infections. Nature Reviews Urology, 14(5),
pp.296–310.
64. Kumar, M.S., Ghosh, S., Nayak, S. and Das, A.P., 2016. Recent
advances in biosensor based diagnosis of urinary tract infection.
Biosensors and Bioelectronics, 80, pp.497–510.
65. Fein, J.E., 1981. Screening of uropathogenic Escherichia coli for
expression of mannose-selective adhesins: Importance of culture
conditions. Journal of Clinical Microbiology, 13(6), pp.1088–1095.
66. Ravinder, P.T., Parija, S.C. and Rao, K.S., 2000. Urinary hydatid
antigen detection by coagglutination, a cost-effective and rapid test
for diagnosis of cystic echinococcosis in a rural or field setting.
Journal of Clinical Microbiology, 38(8), pp.2972–2974.
67. Dong, T. and Zhao, X., 2015. Rapid identification and suscepti-
bility testing of uropathogenic microbes via immunosorbent ATP-
bioluminescence assay on a microfluidic simulator for antibiotic
therapy. Analytical Chemistry, 87(4), pp.2410–2418.
68. Hvolbæk, B., Janssens, T.V., Clausen, B.S., Falsig, H., Christensen,
C.H. and Nørskov, J.K., 2007. Catalytic activity of Au nanoparti-
cles. Nano Today, 2(4), pp.14–18.
69. Ravikumar, S., Gokulakrishnan, R. and Boomi, P., 2012.In vitro
antibacterial activity of the metal oxide nanoparticles against uri-
nary tract infectious bacterial pathogens. Asian Pacific Journal of
Tropical Disease,2(2), pp.85–89.
70. Bhande, R.M., Khobragade, C.N., Mane, R.S. and Bhande, S.,
2013. Enhanced synergism of antibiotics with zinc oxide nanopar-
ticles against extended spectrum -lactamase producers implicated
in urinary tract infections. Journal of Nanoparticle Research, 15(1),
pp.1413–1425.
71. Alshehri, S.M., Aldalbahi, A., Al-Hajji, A.B., Chaudhary, A.A.,
in het Panhuis, M., Alhokbany, N. and Ahamad, T., 2016.Devel-
opment of carboxymethyl cellulose-based hydrogel and nanosilver
composite as antimicrobial agents for UTI pathogens. Carbohy-
drate Polymers, 138, pp.229–236.
72. Al Tameemi, M.B.M., Stan, R., Prisacari, V., Voicu, G., Popa, M.,
Chifiriuc, M.C., Ott, C., Marton, G. and Meghea, A., 2017. Antimi-
crobial performance of nanostructured silica–titania sieves loaded
with izohidrafural against microbial strains isolated from urinary
tract infections. Comptes Rendus Chimie, 20(5), pp.475–483.
73. Shalom, Y., Perelshtein, I., Perkas, N., Gedanken, A. and Banin,
E., 2017. Catheters coated with Zn-doped CuO nanoparticles delay
the onset of catheter-associated urinary tract infections. Nano
Research, 10(2), pp.520–533.
74. Iyer, J.K., Dickey, A., Rouhani, P., Kaul, A., Govindaraju, N.,
Singh, R.N. and Kaul, R., 2018. Nanodiamonds facilitate killing of
intracellular uropathogenic E. coli in an in vitro model of urinary
tract infection pathogenesis. PloS One,13(1), p.e0191020.
75. YokeshBabu, M., JanakiDevi, V., Ramakritinan, C.M., Umarani, R.,
Nagarani, N. and Kumaraguru, A.K., 2013. Biosynthesis of silver
nanoparticles from seaweed associated marine bacterium and its
antimicrobial activity against UTI pathogens. International Journal
of Current Microbiology and Applied Sciences, 2, pp.155–168.
76. Ranjan, P., Das, M.P., Kumar, M.S., Anbarasi, P., Sindhu, S.,
Sagadevan, E. and Arumugam, P., 2013. Green synthesis and char-
acterization of silver nanoparticles from Nigella sativa and its appli-
cation against UTI causing bacteria. Journal of Academia and
Industrial Research, 2, pp.45–49.
77. Ibrahem, K.H., Salman, J.A.S. and Ali, F.A., 2014. Effect of
titanium nanoparticles biosynthesis by lactobacillus crispatus on
3510 J. Nanosci. Nanotechnol. 21, 3495–3512,2021
Devi et al. Herbal Medicine for Urinary Tract Infections with the Blazing Nanotechnology
urease, hemolysin and biofilm forming by some bacteria caus-
ing recurrent UTI in Iraqi women. European Scientific Journal,
ESJ, 10(9), pp.324–338.
78. Sivaraj, R., Rahman, P.K., Rajiv, P., Salam, H.A. and
Venckatesh, R., 2014. Biogenic copper oxide nanoparticles syn-
thesis using Tabernaemontana divaricate leaf extract and its
antibacterial activity against urinary tract pathogen. Spectrochim-
ica Acta Part A: Molecular and Biomolecular Spectroscopy,133,
pp.178–181.
79. Santhoshkumar, J., Kumar, S.V. and Rajeshkumar, S., 2017. Synthe-
sis of zinc oxide nanoparticles using plant leaf extract against uri-
nary tract infection pathogen. Resource-Efficient Technologies,3(4),
pp.459–465.
80. Paralikar, P., Ingle, A.P., Tiwari, V., Golinska, P., Dahm, H.
and Rai, M., 2019. Evaluation of antibacterial efficacy of sulfur
nanoparticles alone and in combination with antibiotics against
multidrug-resistant uropathogenic bacteria. Journal of Environmen-
tal Science and Health, Part A, 54(5), pp.381–390.
81. Divya, M., Kiran, G.S., Hassan, S. and Selvin, J., 2019. Biogenic
synthesis and effect of silver nanoparticles (AgNPs) to combat
catheter-related urinary tract infections. Biocatalysis and Agricul-
tural Biotechnology, 18, pp.101037–101044.
82. Choi, Y.H. and Han, H.K., 2018. Nanomedicines: Current status
and future perspectives in aspect of drug delivery and pharmacoki-
netics. Journal of Pharmaceutical Investigation, 48(1), pp.43–60.
83. Liu, W., Yang, X.L. and Ho, W.W., 2011. Preparation of uniform-
sized multiple emulsions and micro/nano particulates for drug
delivery by membrane emulsification. Journal of Pharmaceutical
Sciences, 100(1), pp.75–93.
84. Onoue, S., Yamada, S. and Chan, H., 2014. Nanodrugs: Phar-
macokinetics and safety. International Journal of Nanomedicine,
14(9), pp.1025–1037.
85. Balogh, L.P., ed., 2017.Nanomedicine in Cancer,NewYork,Jenny
Stanford Publishing, DOI: 10.1201/9781315114361.
86. Singh, K., Ram, S., Nehra, A. and Singh, K.P., 2019. Effect of mag-
netized water on urea-loading efficiency of mesoporous nano-silica:
A seed germination study on wheat crop. Journal of Nanoscience
and Nanotechnology, 19(4), pp.2016–2026.
87. Jepson, R.G., Williams, G. and Craig, J.C., 2012. Cranberries for
preventing urinary tract infections. The Cochrane Database of Sys-
tematic Reviews, 10(10), DOI: 10.1002/14651858.CD001321.pub5.
88. Luczak, T. and Swanoski, M., 2018.A review of cranberry use for
preventing urinary tract infections in older adults. The Consultant
Pharmacist®,33(8), pp.450–453.
89. Guay, D.R., 2009. Cranberry and urinary tract infections.
Drugs,69(7), pp.775–807.
90. Chung, Y.C., Chen, H.H. and Yeh, M.L., 2012.Vinegarfor
decreasing catheter-associated bacteriuria in long-term catheterized
patients: A randomized controlled trial. Biological Research for
Nursing, 14(3), pp.294–301.
91. Harjai, K., Kumar, R. and Singh, S., 2010. Garlic blocks quorum
sensing and attenuates the virulence of Pseudomonas aeruginosa.
FEMS Immunology & Medical Microbiology,58(2), pp.161–168.
92. Madineh, H., Yadollahi, F., Yadollahi, F., Mofrad, E.P. and Kabiri,
M., 2017. Impact of garlic tablets on nosocomial infections in hos-
pitalized patients in intensive care units. Electronic Physician,9(4),
pp.4064–4071.
93. Albrecht, U., Goos, K.H. and Schneider, B., 2007. A randomised,
double-blind, placebo-controlled trial of a herbal medicinal prod-
uct containing Tropaeoli majoris herba (Nasturtium) and Armora-
ciae rusticanae radix (Horseradish) for the prophylactic treatment
of patients with chronically recurrent lower urinary tract infections.
Current Medical Research and Opinion,23(10), pp.2415–2422.
94. Peng, M.M., Fang, Y., Hu, W. and Huang, Q., 2010. The pharma-
cological activities of compound Salvia plebeia granules on treat-
ing urinary tract infection. Journal of Ethnopharmacology,129(1),
pp.59–63.
95. Foxman, B., Manning, S.D., Tallman, P., Bauer, R., Zhang, L.,
Koopman, J.S., Gillespie, B., Sobel, J.D. and Marrs, C.F., 2002.
Uropathogenic Escherichia coli are more likely than commensal
E. coli to be shared between heterosexual sex partners. American
Journal of Epidemiology,156(12), pp.1133–1140.
96. Schlager, T.A., Ashe, K.M. and Hendley, J.O., 1997. The ability of
periurethral Escherichia coli to grow in a voiding system is a key
for the dominance of E. coli cystitis. Microbial Pathogenesis,22(4),
pp.235–240.
97. Karlsson, M., Scherbak, N., Khalaf, H., Olsson, P.E. and Jass, J.,
2012. Substances released from probiotic Lactobacillus rhamno-
sus GR-1 potentiate NF-B activity in Escherichia coli-stimulated
urinary bladder cells. FEMS Immunology & Medical Microbiol-
ogy,66(2), pp.147–156.
98. Grin, P.M., Kowalewska, P.M., Alhazzan, W. and Fox-Robichaud,
A.E., 2013.Lactobacillus for preventing recurrent urinary tract
infections in women: Meta-analysis. Canadian Journal of Urol-
ogy, 20(1), pp.6607–6614.
99. Lorenzo-Gómez, M.F., Padilla-Fernández, B., García-Criado, F.J.,
Mirón-Canelo, J.A., Gil-Vicente, A., Nieto-Huertos, A. and Silva-
Abuin, J.M., 2013. Evaluation of a therapeutic vaccine for the
prevention of recurrent urinary tract infections versus prophylac-
tic treatment with antibiotics. International Urogynecology Jour-
nal,24(1), pp.127–134.
100. Magistro, G. and Stief, C.G., 2019. Vaccine Development for
urinary tract infections: Where do we stand? European Urology
Focu s ,5(1), pp.39–41.
101. Brumbaugh, A.R. and Mobley, H.L., 2012. Preventing urinary tract
infection: Progress toward an effective Escherichia coli vaccine.
Expert Review of Vaccines,11(6), pp.663–676.
102. Karam, M.R.A., Habibi, M. and Bouzari, S., 2019. Urinary tract
infection: Pathogenicity, antibiotic resistance and development of
effective vaccines against uropathogenic Escherichia coli.Molecu-
lar Immunology, 108, pp.56–67.
103. Hasan, S., 2015. A review on nanoparticles: Their synthesis and
types. Research Journal of Recent Sciences, pp.9–11, ISSN-2277-
2502.
104. Jeevanandam, J., Barhoum, A., Chan, Y.S., Dufresne, A. and Dan-
quah, M.K., 2018. Review on nanoparticles and nanostructured
materials: History, sources, toxicity and regulations. Beilstein Jour-
nal of Nanotechnology, 9(1), pp.1050–1074.
105. Machado, S., Pacheco, J.G., Nouws, H.P.A., Albergaria, J.T. and
Delerue-Matos, C., 2015. Characterization of green zero-valent iron
nanoparticles produced with tree leaf extracts. Science of the Total
Environment, 533, pp.76–81.
106. Neubert, R.H., 2011. Potentials of new nanocarriers for dermal and
transdermal drug delivery. European Journal of Pharmaceutics and
Biopharmaceutics,77(1), pp.1–2.
107. ud Din, F., Aman, W., Ullah, I., Qureshi, O.S., Mustapha, O.,
Shafique, S. and Zeb, A., 2017. Effective use of nanocarriers as
drug delivery systems for the treatment of selected tumors. Inter-
national Journal of Nanomedicine, 12, pp.7291–7309.
108. Qian, W.Y., Sun, D.M., Zhu, R.R., Du, X.L., Liu, H. and Wang,
S.L., 2012. pH-sensitive strontium carbonate nanoparticles as new
anticancer vehicles for controlled etoposide release. International
Journal of Nanomedicine, 7, pp.5781–5792.
109. Silva, G.A., 2004. Introduction to nanotechnology and its applica-
tions to medicine. Surgical Neurology, 61(3), pp.216–220.
110. Cho, K., Wang, X.U., Nie, S. and Shin, D.M., 2008.Thera-
peutic nanoparticles for drug delivery in cancer. Clinical Cancer
Research, 14(5), pp.1310–1316.
111. Mohan, S., Oluwafemi, O.S., Kalarikkal, N., Thomas, S. and
Songca, S.P., 2016. Biopolymers–Application in Nanoscience and
Nanotechnology. in Recent Advances in Biopolymers, edited by
Farzana Khan Perveen, London, IntechOpen. pp.47–72.
112. Lombardo, D., Kiselev, M.A. and Caccamo, M.T., 2019.Smart
nanoparticles for drug delivery application: Development of
J. Nanosci. Nanotechnol. 21, 3495–3512, 2021 3511
Herbal Medicine for Urinary Tract Infections with the Blazing Nanotechnology Devi et al.
versatile nanocarrier platforms in biotechnology and nanomedicine.
Journal of Nanomaterials, 2019, pp.1–27.
113. Xu, Z.P., Zeng, Q.H., Lu, G.Q. and Yu, A.B., 2006. Inorganic
nanoparticles as carriers for efficient cellular delivery. Chemical
Engineering Science,61(3), pp.1027–1040.
114. Li, Y.L. and Sun, B.H., 2019. Nano-delivery materials: Review
of development and application in drug/gene transport. in Key
Engineering Materials, Trans Tech Publications Ltd. Vol. 803,
pp.158–166.
115. Ealias, A.M. and Saravanakumar, M.P., 2017. A Review on the
Classification, Characterisation, Synthesis of Nanoparticles and
Their Application. IOP Conference Series: Materials Science and
Engineering, November; Vol. 263, pp.32019–32033.
116. Ahmed, S., Ahmad, M., Swami, B.L. and Ikram, S., 2016.Areview
on plants extract mediated synthesis of silver nanoparticles for
antimicrobial applications: A green expertise. Journal of Advanced
Research, 7(1), pp.17–28.
117. Cho, E.J., Holback, H., Liu, K.C., Abouelmagd, S.A., Park, J.
and Yeo, Y., 2013. Nanoparticle characterization: State of the
art, challenges, and emerging technologies. Molecular Pharmaceu-
tics, 10(6), pp.2093–2110.
118. Ramanathan, A.A. and Aqra, M.W., 2019. An overview of the green
road to the synthesis of nanoparticles. Journal of Materials Science
Research and Reviews, 2(3), pp.1–11.
119. GuhaSarkar, S. and Banerjee, R., 2010. Intravesical drug delivery:
Challenges, current status, opportunities and novel strategies. Jour-
nal of Controlled Release, 148(2), pp.147–159.
120. Jahanshahi, M. and Babaei, Z., 2008. Protein nanoparticle:
A unique system as drug delivery vehicles. African Journal of
Biotechnology, 7(25), pp.4926–4934.
121. Zhang, L., Pornpattananangkul, D., Hu, C.M. and Huang, C.M.,
2010. Development of nanoparticles for antimicrobial drug delivery.
Current Medicinal Chemistry, 17(6), pp.585–594.
122. Karim, M., Shetty, J., Islam, R.A., Kaiser, A., Bakhtiar, A. and
Chowdhury, E.H., 2019. Strontium sulfite: A new pH-responsive
inorganic nanocarrier to deliver therapeutic siRNAs to cancer cells.
Pharmaceutics, 11(2), pp.89–114.
123. Emeje, M.O., Obidike, I.C., Akpabio, E.I. and Ofoefule, S.I., 2012.
Nanotechnology in Drug Delivery. in Recent Advances in Novel
Drug Carrier Systems, edited by Ali Demir Sezer, London, Inte-
chOpen. pp.70–106.
124. Hagens, W.I., Oomen, A.G., de Jong, W.H., Cassee, F.R. and Sips,
A.J., 2007. What do we (need to) know about the kinetic properties
of nanoparticles in the body? Regulatory Toxicology and Pharma-
cology, 49(3), pp.217–229.
125. Kroll, A., Pillukat, M.H., Hahn, D. and Schnekenburger, J., 2009.
Current in vitro methods in nanoparticle risk assessment: Limi-
tations and challenges. European Journal of Pharmaceutics and
Biopharmaceutics, 72(2), pp.370–377.
126. Bonifacio, B.V., da Silva, P.B., dos Santos Ramos, M.A., Negri,
K.M.S., Bauab, T.M. and Chorilli, M., 2014. Nanotechnology-
based drug delivery systems and herbal medicines: A review. Inter-
national Journal of Nanomedicine,9, pp.1–15.
127. Fernandez-Moure, J.S., Evangelopoulos, M., Colvill, K., Van Eps,
J.L. and Tasciotti, E., 2017. Nanoantibiotics: A new paradigm for
the treatment of surgical infection. Nanomedicine,12(11), pp.1319–
1334.
128. Nirmal, J., Chuang, Y.C., Tyagi, P. and Chancellor, M.B., 2012.
Intravesical therapy for lower urinary tract symptoms. Urological
Science, 23(3), pp.70–77.
129. Alexis, F., Rhee, J.W., Richie, J.P., Radovic-Moreno, A.F., Langer,
R. and Farokhzad, O.C., 2008. New frontiers in nanotechnology
for cancer treatment. In Urologic Oncology: Seminars and Original
Investigations, 26(1), pp.74–85.
130. Rawat, M., Singh, D., Saraf, S. and Saraf, S., 2006. Nanocarriers:
Promising vehicle for bioactive drugs. Biological and Pharmaceu-
tical Bulletin,29(9), pp.1790–1798.
131. Potgieter, M., Bester, J., Kell, D.B. and Pretorius, E., 2015. The dor-
mant blood microbiome in chronic, inflammatory diseases. FEMS
Microbiology Reviews,39(4), pp.567–591.
132. Van Giau, V., An, S.S.A. and Hulme, J., 2019. Recent advances in
the treatment of pathogenic infections using antibiotics and nano-
drug delivery vehicles. Drug Design, Development and Therapy, 13,
pp.327–343.
Received: 31 December 2018. Accepted: 28 September 2019.
3512 J. Nanosci. Nanotechnol. 21, 3495–3512,2021
