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Review Article
Combating Pathogenic Microorganisms Using Plant-Derived
Antimicrobials: A Minireview of the Mechanistic Basis
Abhinav Upadhyay, Indu Upadhyaya,
Anup Kollanoor-Johny, and Kumar Venkitanarayanan
Department of Animal Science, University of Connecticut, 3636 Horsebarn Hill Road Extension, Unit 4040, Storrs, CT 06269, USA
Correspondence should be addressed to Kumar Venkitanarayanan; kumar.venkitanarayanan@uconn.edu
Received April ; Revised August ; Accepted August ; Published September
Academic Editor: Vasilis P. Valdramidis
Copyright © Abhinav Upadhyay et al. is is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
e emergence of antibiotic resistance in pathogenic bacteria has led to renewed interest in exploring the potential of plant-
derived antimicrobials (PDAs) as an alternative therapeutic strategy to combat microbial infections. Historically, plant extracts
have been used as a safe, eective, and natural remedy for ailments and diseases in traditional medicine. Extensive research in
the last two decades has identied a plethora of PDAs with a wide spectrum of activity against a variety of fungal and bacterial
pathogens causing infections in humans and animals. Active components of many plant extracts have been characterized and are
commercially available; however, research delineating the mechanistic basis of their antimicrobial action is scanty. is review
highlights the potential of various plant-derived compounds to control pathogenic bacteria, especially the diverse eects exerted
by plant compounds on various virulence factors that are critical for pathogenicity inside the host. In addition, the potential eect
of PDAs on gut microbiota is discussed.
1. Introduction
Human population growth with its global eects on the
environment over the past million years has resulted in
the emergence of infectious diseases [,]. Development of
agriculture further contributed to this, since these infections
could only be sustained in large and dense human popula-
tions []. e discovery of antibiotics during the twentieth
century coupled with signicant advances in antimicro-
bial drug development improved human health through
improved treatment of infections [,]. However, prolonged
use of antibiotics led to bacterial adaptation, resulting in the
development of multidrug resistance in bacteria [,–]. is
has signicantly limited the ecacy of antibiotics, warranting
alternative strategies to combat microbial infections.
e persistence of bacteria in the environment and their
interaction with humans is central to most infections and
illnesses. Bacterial illnesses are orchestrated by means of
an array of virulence factors that facilitate various aspects
of their pathophysiology critical for disease in the host
[]. ese include adhesins and membrane proteins that
mediate bacterial attachment, colonization, and invasion of
host cells. In addition, microbial toxins cause host tissue
damage,andbacterialcellwallcomponentssuchascapsular
polysaccharide confer resistance against host immune system
[,]. Biolm formation and spore forming capacity are
additional virulence factors that help in the persistence of
pathogens in harsh environmental conditions.
Since ancient times, plants have played a critical role in
thedevelopmentandwell-beingofhumancivilization.A
plethora of plant products have been used as food preserva-
tives, avor enhancers, and dietary supplements to prevent
food spoilage and maintain human health. In addition,
plant extracts have been widely used in herbal medicine,
both prophylactically and therapeutically for controlling
diseases. e antimicrobial activity of several plant-derived
compounds has been previously reported [–], and a wide
array of active components have been identied []. A
majority of these compounds are secondary metabolites and
are produced as a result of reciprocal interactions between
plants, microbes, and animals []. ese compounds do
not appear to play a direct role in plant physiology [];
however they are critical for enhancing plant tness and
defense against predation []. e production of secondary
Hindawi Publishing Corporation
BioMed Research International
Volume 2014, Article ID 761741, 18 pages
http://dx.doi.org/10.1155/2014/761741
BioMed Research International
metabolites is oen restricted to a limited set of species within
a phylogenetic group as compared to primary metabolites
(amino acids, polysaccharides, proteins, and lipids), which
are widespread in the plant kingdom []. Also, they are
generated only during a specic developmental period of
plant growth at micro- to submicromolar concentration [,
].
e primary advantage of using plant-derived antimicro-
bials(PDAs)fortherapeuticpurposesisthattheydonot
exhibitthesideeectsoenassociatedwithuseofsynthetic
chemicals []. In addition, to the best of our knowledge, no
reports of antimicrobial resistance to these phytochemicals
have been documented, probably due to their multiple mech-
anisms of action which potentially prevent the selection of
resistant strains of bacteria. e marked antimicrobial eect,
nontoxic nature, and aordability of these compounds have
formed the basis for their wide use as growth promoters in
thelivestockandpoultryindustry,eectiveantimicrobials
and disinfectants in the food industry, components of herbal
therapy in veterinary medicine, and source for development
of novel antibiotics in pharmaceutics.
e antimicrobial properties of various plant compounds
that target cellular viability of bacteria have been adequately
discussed previously [,–], but very few reviews have
highlighted the eects of these compounds in modulating
various aspects of bacterial virulence, critical for patho-
genesis in the host. In this review, we have focused on a
wide array of PDAs, with special emphasis on the diverse
biological eects exerted by these compounds on bacterial
virulence. e important classes of plant compounds and
selected antimicrobial mechanisms have been discussed.
2. Plant-Derived Antimicrobials
Most plant-derived compounds are produced as secondary
metabolitesandcanbeclassiedbasedontheirchemical
structure, which also inuences their antimicrobial property
(Table ). e major groups of phytochemicals are presented
here.
2.1. Phenolics and Polyphenols. ese are a diverse group of
aromatic secondary metabolites involved in plant defense.
ey consist of avonoids, quinones, tannins, and coumarins
[–].
2.1.1. Flavonoids. Flavonoids are pigmented compounds
found in fruits and owers of plants and mainly consist of
avone, avanones, avanols, and anthocyanidins [,].
ey facilitate pollination by acting as chemoattractants for
insects, modulate plant physiology by signaling to benecial
microbiota in rhizosphere, and protect plants against pre-
dation due to their antimicrobial nature []. e marked
antimicrobial property of avonoids against a variety of
bacterial [–]andfungalpathogens[]ismediatedby
their action on the microbial cell membranes []. ey
interact with membrane proteins present on bacterial cell wall
leading to increased membrane permeability and disruption.
Catechins belonging to this group exhibit inhibitory activity
against both Gram-positive and Gram-negative organisms
[].
2.1.2. Quinones. Quinones are organic compounds consisting
of aromatic rings with two ketone substitutions. Quinones
areknowntocomplexirreversiblywithnucleophilicamino
acids in protein, oen leading to their inactivation and
loss of function []. e major targets in the microbial
cell include surface-exposed adhesin proteins, cell wall
polypeptides, and membrane-bound enzymes []. Quinone
such as anthraquinone from Cassia italica was found to be
bacteriostatic against pathogenic bacteria such as Bacillus
anthracis,Corynebacterium pseudodiphthericum,andPseu-
domonas aeruginosa and bactericidal against Burkholderia
pseudomallei [].
2.1.3. Tannins. Tannins are a group of water-soluble oligo-
meric and polymeric polyphenolic compounds, with signif-
icant astringent properties. ey are present in the majority
of plant parts, including bark, leave, fruits, and roots [].
ey are widely used in leather industry, in food industry,
and, as antimicrobials, in healthcare industry []. e mode
of antimicrobial action of tannins is potentially due to
inactivation of microbial adhesins and cell envelope transport
proteins [–]. Besides their ecacy against bacteria,
tannins have been reported to be inhibitory on fungi and
yeasts [,].
2.1.4. Coumarins. Coumarins are a group of aromatic ben-
zopyrones consisting of fused benzene and alpha pyrone rings
[]. Approximately, coumarins have been identied
since []andareusedasantithromboticandanti-
inammatory compounds []. Recently, coumarins such
as scopoletin and chalcones have been isolated as antitu-
bercular constituents of the plant Fatoua pilosa []. In
addition, phytoalexins, which are hydroxylated derivatives
of coumarins, which are produced in plants in response
to microbial infections, have been found to exert marked
antifungal activity.
2.2. Alkaloids. Alkaloids are a group of heterocyclic nitroge-
nous compounds with broad antimicrobial activity. Mor-
phine and codeine are the oldest known compounds in
this group []. Diterpenoid alkaloids, commonly isolated
from Ranunculaceae or buttercup family of plants, are found
to possess antimicrobial properties []. e mechanism
of action of aromatic planar quaternary alkaloids such as
berberine and harmane is attributed to their ability to inter-
calate with DNA thereby resulting in impaired cell division
and cell death [].
2.3. Terpenoids. Terpenes represent one of the largest and
most diverse groups of secondary metabolites consisting
of ve carbon isoprene structural units linked in various
congurations []. e action of terpene cyclase enzymes
alongwithsubsequentoxidationandstructuralrearrange-
ment imparts a rich diversity to the group with over
, members isolated so far []. e major groups
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T : Chemical structure, examples, and antimicrobial spectrum of major groups of plant-derived antimicrobials.
Plant-derived
antimicrobials Chemical structure Examples∗Selected antimicrobial
spectrum References
Phenolics and polyphenols
Flavonoids
R
O
HO
O
R
R
R
RR
R
(Beecher, ) []
Flavones(apigenin, chrysin,
rutin)
Flavanones(naringenin,
setin)
Catechins(catechin,
epicatechin)
Anthocyanins(cyanidin,
petunidin)
Listeria monocytogenes
Staphylococcus aureus
Escherichia coli O:H
Salmonella enterica
Vibr io ch olera
Pseudomonas aeruginosa
Acinetobacter baumannii
Klebsiella pneumonia
Aspergillus avus
Penicillium sp.
Cladosporium sp.
Beecher, []; Chye
and Hoh, [];
Orhan et al., [];
Rattanachaikunsopon and
Phumkhachorn,[];
Ozc¸eliketal.,[];
Cushnie and Lamb,
[]
Quinones
O
O
(Cowan, ) []
Anthraquinone
Benzoquinone
Naphthoquinone
Plastoquinone
Pyrroloquinoline quinone
Staphylococcus aureus
Pseudomonas aeruginosa
Bacillus subtilis
Cryptococcus neoformans
Ignacimuthu et al.,
[]; Singh et al.,
[]; Cowan, []
Tannins
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
HO
HO
HO O
O
OR
R
R
(Scalbert, ) []
Tannic acid
Gallic acid
Proanthocyanidins
Staphylococcus aureus
Bacillus cereus
Listeria monocytogenes
Salmonella enterica
Campylobacter jejuni
Engels et al., [];
Scalbert, []
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T : C ontinue d.
Plant-derived
antimicrobials Chemical structure Examples∗Selected antimicrobial
spectrum References
Coumarins OO
(Cowan, ) []
Ammoresinol
Ostruthin
Anthogenol
Agasyllin
Staphylococcus aureus
Listeria monocytogenes
Escherichia coli O:H
Salmonella Typhimurium
Salmonella Enteritidis
Vibrio parahaemolyticus
Basile et al., [];
Ulate-Rodr´
ıguez et al.,
[]; Venugopala et al.,
[]; Saleem et al.,
[]; Cowan,
[]
Alkaloids
Terp enoid s
CH3
H2C
PP
O
O
O
O
O−O−
O−
(Ulubelen, ) []
Carotenoids
Terpinene
Isopentenyl pyrophosphate
Staphylococcus aureus
Pseudomonas aeruginosa
Vibr io ch olera
Salmonella typhi
Ulubelen, []; Bach
et al., []; Batista
et al., []; Mathabe
et al., []
Lectins and
polypeptides
Concanavalin A
(Hardman and Ainsworth, ) []
Concanavalin A
Wheat germ agglutinin
(WGA)
Aleuria aurantia lectin
(AAL)
Staphylococcus aureus
Bacillus subtilis
Escherichia coli
Pseudomonas aeruginosa
Candida albicans
Hardman and Ainsworth,
[]; Petnual et al.,
[]; Kheeree et al.,
[]; Peumans and
Van Da mm e, [ ]
∗e examples discussed in the table are only representative for the group. For an extended list of examples of each group, the readers are requested to peruse review articles in the References section and other
sources.
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consist of diterpenes, triterpenes, tetraterpenes as well as
hemiterpenes, and sesquiterpenes []. When the com-
pounds contain additional elements, frequently oxygen,
they are termed terpenoids. Compounds such as menthol
and camphor (monoterpenes), farnesol and artemisinin
(sesquiterpenoids) are terpenoids synthesized from acetate
units and share their origins and chemical properties with
fatty acids []. Sesquiterpenoids are known to exhibit
bactericidal activity against Gram-positive bacteria, includ-
ing M. tuberculosis [,]. e mechanism of antimi-
crobial action of terpenoids is not clearly dened, but it
is attributed to membrane disruption in microorganisms
[].
2.4. Lectins and Polypeptides. In , it was rst reported
thatpeptidescouldbeinhibitoryonmicroorganisms[].
Although recent interest has chiey focused on studying
anti-HIV peptides and lectins, the inhibition of bacteria and
fungi by these molecules has long been known []. e
mechanism of action of peptides and lectins is presumed to
be due to the formation of ion channels in the microbial
membrane [] or due to competitive inhibition of adhesion
of microbial proteins to host polysaccharide receptors [].
Lectin molecules are larger and include mannose-specic
molecules obtained from an array of plants []. Lectins such
as MAP from bitter melon [], GAP from Gelonium
multiorum [], and jacalin [] are inhibitory on viral pro-
liferation, including HIV and cytomegalovirus by potentially
inhibiting viral interaction with critical host cell components.
Duetotheversatileantifungal,antibacterial,andantiviral
functions delivered by these compounds, it is advantageous
to investigate in depth their exact mechanism of action.
3. Critical Antimicrobial Properties of PDAs
3.1. Membrane Disruption and Impaired Cellular Metabolism.
Although the exact mechanisms by which PDAs exert their
antimicrobial action are not well dened, several potential
methods have been reported. ese include disruption of
bacterial cell membrane leading to loss of membrane poten-
tial, impaired ATP production, and leakage of intracellular
contents [,]. Furthermore, chelation of metal ions,
inhibition of membrane-bound ATPase, and altered mem-
brane permeability brought about by PDAs aect normal
physiology of bacteria and cause cell death [,,,–
]. Plant-derived antimicrobials such as carvacrol, thymol,
eugenol,andcatechinsactbydisruptionofcellmembrane,
followed by the release of cell contents and loss of ATP [,,
,]. However, cinnamaldehyde has been reported to result
in the depletion of intracellular ATP by inhibiting ATPase
dependent energy metabolism along with the inhibition of
glucoseuptakeandutilization[,,,]. Lysis of cell wall
has also been documented in bacteria exposed to phenolic
compounds [,].
3.2. Antibiolm Activity. Bacterial biolms are surface-asso-
ciated microbial communities enclosed in a self-generated
exopolysaccharide matrix [,]. ey are a cause of
major concern, especially in the food industry and hospital
environments due to their recalcitrance to commonly
used antimicrobials and disinfectants [–], thereby
resulting in human illnesses, including endocarditis,
cystic brosis, and indwelling device-mediated infections
[].
Extensive research exploring the potential of alternative
strategies for microbial biolm control has highlighted the
ecacy of several PDAs in controlling biolm formation
in major pathogens, including Listeria monocytogenes [],
Staphylococcus aureus [–], Pseudomonas aeruginosa [,
], Escherichia coli [,], and Klebsiella pneumoniae
[]. Trans -cinnamaldehyde, an aromatic aldehyde obtained
from bark of cinnamon trees, was found to inhibit biolm
formation and inactivate mature biolm of Cronobacter
sakazakii on feeding bottle coupons, stainless steel surfaces,
and uropathogenic E. coli on urinary catheters [,].
Similarly, terpenes such as carvacrol, thymol, and geraniol
and essential oils of Cymbopogon citratus and Syzygium
aromaticum were found to exhibit marked antibiolm activity
against both fungal [–]andbacterialbiolms[,
,] encountered in food processing environments and
biomedical settings.
As observed in antibiotics [–], PDAs at subin-
hibitory concentrations (SICs, concentrations not inhibiting
thegrowthofmicrobes)arereportedtomodulatebacte-
rial gene transcription [,,–], which could be
a contributing factor to their antibiolm property. In a
study by Amalaradjou and Venkitanarayanan [], trans-
cinnamaldehyde was found to modulate the transcription
of genes critical for biolm formation, motility, attachment,
and quorum sensing in C. sakazakii. Similarly, Brackman
and coworkers [] observed the inhibitory eects of trans-
cinnamaldehyde on biolms of Vibri o spp. ese authors
found that trans-cinnamaldehyde was able to mitigate autoin-
ducer based quorum sensing and biolm formation without
inhibiting bacterial growth, probably due to its eect on gene
transcription. Similar transcription modulatory eects have
been observed in other major pathogens such as Salmonella
[]andP. a e r u g i n o s a [] following exposure to PDAs.
Since quorum sensing is one of the key processes involved in
cell-to-cell communication and social behavior in microbes,
the aforementioned reports could provide new insights into
the development of novel therapeutics targeting key physio-
logical processes in microbes.
Despite exhibiting eective antibiolm properties, the use
of PDAs has been thwarted by various confounding factors
suchastherequirementformorecontacttime,diculty
in administration, and organoleptic considerations when
used on food contact surfaces. erefore several researchers
have investigated the ecacy of new delivery methods
such as biodegradable polymers, micellar encapsulation,
and polymeric lms to potentiate the antibiolm action
of plant compounds. For example, micellar encapsulated
eugenol and carvacrol were found to inhibit and inacti-
vate L. monocytogenes and E. coli O:H colony biolms
[]. Similarly, reduced biolm formation was observed on
polymeric lms containing carvacrol and cinnamaldehyde
[]. Nanoparticle-based drug delivery systems have been
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more frequently investigated for potentiating the antimi-
crobial ecacies of drugs []. e major advantages of
nanoparticle-based drug delivery include sustained release,
higher stability, and enhanced interaction of active ingredi-
ents with pathogens at their molecular level [], thereby
potentiating their antimicrobial action. e antimicrobial
potential of nanoparticles containing plant-derived com-
pounds such as trans-cinnamaldehyde, eugenol [], and
resveratrol []oressentialoilofNigella sativa []and
garlic [] has been recently investigated. ese researchers
found that nanoparticle formulations were more stable and
highly eective in inhibiting the growth of major bacterial
pathogens, including Salmonella and Listeria spp. Currently
research is underway to investigate the potential of various
nanoparticle-based delivery systems containing PDAs []
for eradicating biolms from hospital devices [] and food
processing environments []. In a recent study, Iannitelli
and coworkers [] prepared carvacrol encapsulated poly
(DL-lactide-co-glycolide) (PLGA) nanoparticles and found
that they were signicantly eective in inactivating microbial
biolms of Staphylococcus epidermidis. In another study,
PLGA containing cinnamaldehyde and carvacrol coatings
were found to inhibit biolms of E. coli,S. aureus,andP.
aeruginosa [].
3.3. Inhibiting Bacterial Capsule Production. Polysaccharide
capsule is an important virulence determinant [,]in
many pathogenic bacteria, including Streptococcus pneumo-
nia [–], S. aureus [], K. pneumoniae [], and
Bacillus anthracis []. It protects bacteria from phagocytosis
[], thereby enhancing bacterial survival inside the host
[]. In addition, the presence of a capsule enhances bacte-
rial adhesion and biolm formation [] in the environment
[,]. Bacterial capsule has also been observed to cause
pathology in plants. For example, capsular polysaccharide
of Pseudomonas solanacearum was found to occlude xylem
vessels resulting in plant death []. Since salicylic acid is
a signal molecule involved in plant defense [], several
researchers have investigated the eect of salicylic acid
[] or its derivatives such as sodium salicylate [], bis-
muth subsalicylate [], and bismuth dimercaprol []on
modulating bacterial capsule production. ese researchers
found that salicylic acid or its derivatives were eective in
signicantly reducing capsule production by modulating the
expression of global regulators controlling capsular synthesis
in S. aureus. Similar inhibitory eects have been observed
with sub-MICs and MICs of various antibiotics [–].
us, plant-derived compounds represent a valuable resource
for the development of therapeutics targeting bacterial cap-
sule production.
3.4. Increasing Antibiotic Susceptibility in Drug Resistant
Bacteria. As the understanding of antimicrobial resistance
mechanisms in pathogens is increasing, multifold strategies
to combat infections and reverse bacterial antibiotic resis-
tance are being explored. Many researchers have reported
PDAs as potential resistance modulating compounds, in
addition to their inherent antimicrobial nature. In a study
by Brehm-Stecher and Johnson [], low concentrations
of sesquiterpene such as nerolidol, bisabolol, and apritone
increased bacterial sensitivity to multiple antibiotics, includ-
ing ciprooxacin, clindamycin, tetracycline, and vancomycin.
Similarly, Dickson et al. [] reported that plant extracts
from Mezoneuron benthamianum,Securinega virosa,and
Microglossa pyrifolia increased the susceptibility of major
drug resistant fungi such as Tri ch ophyton spp. and Microspo-
rum gypseum and bacteria such as Salmonella spp., Klebsiella
spp., P. a e r u g i n o s a ,andS. aureus to noroxacin. In addition,
geraniol (present in essential oil of Helichrysum italicum)was
found to restore the ecacy of quinolones, chloramphenicol,
and 𝛽-lactams against multidrug resistant pathogens, includ-
ing Acinetobacter baumannii []. Similar synergism was
observed between antibiotics and various other medicinal
plant extracts, including those of Camellia sinensis [], Cae-
salpinia spinosa [], oil of Croton zehntneri [], carvacrol
[], and baicalein, the active component derived from
Scutellaria baicalensis []. is modulatory eect of plant
compoundsispotentiallyduetotheattenuationofthreemain
resistance strategies employed by drug resistant pathogens to
survive the action of antibiotics, namely, enzymatic degra-
dation of antibiotics [], alteration of antibiotic target site
[], and eux pumps []. In addition, recent reports
suggest that the combination therapy of antibiotics with
PDAs acts through inhibition of multiple targets in various
pathways critical for the normal functioning or virulence of
the bacterial cell.
Generation of 𝛽-lactamase enzymes is an example of
microbial strategy that is responsible for resistance to 𝛽-
lactam antibiotics []. Several plant compounds have been
identied with inhibitory activity towards 𝛽-lactamases [].
Gangou´
e-Pi´
eboji and coworkers [] screened medicinal
plants from Cameroon and found that extracts from Garcinia
lucida and Bridelia micrantha exhibited signicant inhibitory
activity towards 𝛽-lactamases. Similarly, epigallocatechin gal-
late was found to inhibit penicillinase activity, thus increasing
the sensitivity of S. aureus to penicillin []andaugmenting
the antimicrobial properties of ampicillin and sulbactam
against Methicillin resistant S. aureus (MRSA).
Numerous studies in the past two decades have shown
theecacyofPDAsaspotenteuxpumpinhibitors
against Gram-positive microbes [–]. Gram-negative
bacteria pose an even greater challenge owing to the pres-
ence of potent eux pumps, especially, AcrAB-TolC pumps
[]. In a recent investigation, ve PDAs, namely, trans-
cinnamaldehyde, 𝛽-resorcylic acid, carvacrol, thymol, and
eugenol, or their combinations were found to increase the
sensitivity of Salmonella enterica serotype Typhimurium
phagetypeDTtoveantibiotics[]. Since the mecha-
nism of antimicrobial resistance in Salmonella Typ hi murium
DT is mainly mediated by interaction between specic
transporters of antibiotics and AcrAB-TolC eux pump, the
aforementioned plant compounds could be acting through
modulationoftheseeuxpumpstoincreasetheantibiotic
sensitivity of the pathogen [].
3.5. Attenuating Bacterial Virulence. e pathophysiology
of microbial infection in a host is mediated by multiple
virulence factors, which are expressed at dierent stages of
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infection to cause the disease. Reducing production of these
virulence factors could control infections in humans. With
major advancement in the elds of comparative genomics,
transcriptomics, and proteomics, a better understanding of
the key virulence mechanisms of pathogenic bacteria has
been achieved. us, virulence factors are the prime targets
for therapeutic interventions and vaccine development [].
Quorum sensing controls the expression of genes encoding
various virulence factors in many microorganisms [,].
A growing body of evidence suggests that plants produce
antiquorum sensing compounds that interfere with cell-to-
cell communication, thereby downregulating the expression
of virulence genes in microbes [–]. We previously
reported that trans-cinnamaldehyde reduced the expression
of luxR, which codes for transcriptional regulator of quorum
sensing in C. sakazakii []. Similarly, Bodini and coworkers
found that garlic extract and p-coumaric acid inhibited quo-
rum sensing in quorum sensing reporter strains, indicating
that plant compounds potentially modulate virulence by
aecting quorum sensing in microbes.
For the majority of enteric pathogens, adhesion to and
invasion of intestinal epithelium are critical for virulence and
infection in a host. Specic proteins contribute to adhesion
and invasion in various microbes. For example, Inl A and
Inl B are surface proteins that facilitate receptor-mediated
entry of L. monocytogenes in intestinal cells []. Several
PDAshavebeenshowntoreducethesevirulenceattributes
in major food-borne pathogens such as L. monocytogenes
[], uropathogenic E. coli [], and Salmonella enterica
serovar Enteritidis [] by downregulating the expression of
virulence genes. In addition, reduction in capsule production
has been documented in K. pneumoniae on exposure to PDAs
[], which aects its virulence and survival inside the host.
ese results highlight the ability of plant compounds to
successfully target virulence factors critical for pathogenicity
andpavethewayforthedevelopmentofcompoundsthat
target bacterial virulence.
3.6. Reducing Toxin Production. Microbial toxins are chem-
ical compounds critical for virulence and pathogenesis in
the host and therefore are prime targets for therapeutic
interventions. Microbial toxins include exotoxins (secreted
by the bacteria) and endotoxins (released aer bacterial
lysis), whereas mycotoxins are toxic secondary metabolites
produced by fungi with diverse chemical structures and
biological activities causing a variety of illnesses in humans.
e drugs of choice for treating bacterial infections have been
antibiotics; however the use of antibiotics to kill toxigenic
microorganisms has several disadvantages such as resistance
development [], disruption of normal microbiota [],
and enhanced pathogenesis due to increased toxin produc-
tion and cell lysis as observed in E. coli O:H [,].
Moreover, toxin-mediated pathogenesis can continue in the
host even aer bacterial clearance []. erefore, antibiotics
in general are contraindicated to treat toxigenic organisms
and it is benecial to employ an alternative approach to
counteract the toxin-mediated virulence of pathogens.
In the past, plant extracts and their active molecules have
proven eective against bacterial toxins produced by Vibr io
spp., S. aureus,E. coli, and fungal toxins from Aspergillus spp.
For example, a natural plant-derived dihydroisosteviol has
been observed to prevent cholera toxin-mediated intestinal
uid secretion []. Plant polyphenols such as RG-tannin
and apple phenols have been reported to inhibit ADP-
ribosyltransferase activity critical for cholera toxin action
[,]. ese researchers also observed a reduction in the
toxin induced uid accumulation in mouse ileal loops. In a
recentstudybyYamasakietal.[],extractsfromspicessuch
asredchilli,sweetfennel,andwhitepepperwerefoundto
substantially inhibit the production of cholera toxin. ese
researchers found that capsaicin was an important compo-
nent among the tested fractions and signicantly reduced the
expression of major virulence genes of V. ch oler a e,including
ctxA,tcpA,andtoxT.Similarly,eugenol,anessentialoilfrom
clove, was observed to signicantly reduce the production
of S. aureus 𝛼-hemolysin, enterotoxins (SEA, SEB), and
toxic shock syndrome toxin []. Transcriptional analysis
conducted by these researchers revealed a reduction in the
expression of critical virulence genes (sea, seb, tst, and hla)
involved in various aspects of S. aureus toxin production.
Similarly, a compound from olive, -hydroxytyrosol, was
found to successfully inactivate S. aureus endotoxin produc-
tion in vitro [].
Enterohemorrhagic E. coli (EHEC) is responsible for
causing severe human infections, characterized by hemor-
rhagic colitis and hemorrhagic uremic syndrome []. In
arecentstudybyDoughariandcoworkers[], extracts
of Curtisia dentata were found to inhibit expression of
vtx1 and vtx2 genes in EHEC. e extracts from this
plant have been traditionally used as an antidiarrheal agent
[]. Similar verotoxin inhibitory activity was observed in
other plant extracts such as Haematoxylon brasiletto [],
Limonium californicum (Boiss.), Cupressus lusitanica,Salvia
urica Epling, and Jussiaea peruviana L. []. Inactivation
of Shiga toxins by antitoxin antibodies []andbycertain
syntheticcarbohydrateandpeptidecompoundsdesignedto
compete with the active site of the toxin for receptor sites
on cell membranes has also been investigated [–].
Qui˜
nones and coworkers [] found that grape seed and
grape pomace extracts exhibited strong anti-Shiga toxin-
activity and conferred cellular protection against Shiga toxin-
. Likewise, Daio (Rhei rhizoma), apple, hop bract, and green
tea extracts have been shown previously to inhibit the release
of Shiga toxin from E. coli O:H [,].
Aatoxins, produced by Aspergillusavus,A.parasiticus,
A. nomius, A. tamari, A. bombycis, and A. pseudotamarii,
cause both acute and chronic toxicity in humans and animals
[–]. Common food products associated with myco-
toxicosis include peanuts, corn grain, cottonseed [,],
chicken meat []cheese[], canned mushrooms [],
raw milk [,], and pork [,]. Several studies have
highlighted the ecacy of essential oils in reducing myco-
toxin production. Crude aqueous extracts of garlic, carrot,
and clove have been shown to exert a signicant inhibitory
eect on aatoxin production in rice []. Capsanthin and
capsaicin, the coloring and pungent ingredients of red chilli
(Capsicum annum), completely inhibited both the growth
and toxin production in A. avus []. Mahmoud []
BioMed Research International
studiedtheeectofseveralplantessentialoilsongrowthand
toxin production of A. avus and found that ve essential
oils, namely, geraniol, nerol, citronellol, cinnamaldehyde, and
thymol, completely suppressed the growth of A. avus and
prevented aatoxin synthesis in a liquid medium. Similarly,
curcumin and essential oil from Curcuma longa have also
been reported to inhibit A. avus toxin production []. In
another study, cumin and clove oils have been found to exert
inhibitory eects on toxin production in A. parasiticus [],
wherein aatoxin production was decreased by %. Similar
ndings have been observed with ochratoxin-producing
aspergilli, where essential oil from wild thyme reduced
ochratoxin production by more than % []. In addition,
essential oils have been found to inhibit spore germination
in toxin producing Aspergillus species []. In a recent study,
Kumar and coworkers [] demonstrated that amaryllin, a
-kDa antifungal protein from Amaryllis belladonna bulbs,
exerts signicant inhibitory eect against toxin producing A.
avus and Fusarium oxysporum. e aforementioned studies
collectively suggest that plant polyphenols and other plant
compounds are potential agents that can be used to protect
humans against toxin-mediated food-borne diseases.
3.7. Benecial Eects on Host Immune System. Pioneering
research has demonstrated the existence of intriguing par-
allels between plant and animal immune responses against
microbial infections. ese include recognition of invari-
ant pathogen-associated molecular patterns (PAMPs) [],
apoptosis of infected cells [,], and production of
antimicrobial peptides [,]. However, unlike microbe-
specic immune response in animals, plants depend on
innate immunity of individual cells coupled with signals
emanating from the site of infection [,–]tocombat
infections. is is mediated by the production of a wide
variety of low molecular weight secondary metabolites [,
]. A mounting body of evidence suggests that plants
extracts, in addition to their role in plant defense, exert
immune-modulatory eects in animals [,]andare
increasingly being used for treating inammatory diseases,
allergy, and arthritis []. For example, tea tree [,]
and lavender oils [] were found to ameliorate allergy
symptoms by reducing histamine release [,]and
cytokine production []. e immune-modulatory eects
of many PDAs have been demonstrated in mouse, chicken,
and human cell lines [–]. Since the majority of the
entericpathogenscolonizeandinvadethegutepithelium,
followed by systemic spread via macrophages resulting in
infection, the intestinal mucosal immune response (IMIS)
is critical for conferring protection against such bacterial
infections. A growing body of evidence suggests that PDAs
in addition to attenuating bacterial virulence modulate IMIS
[,] through both nonspecic inammatory response
and antigen specic adaptive interactions in the intestine,
thereby aecting pathogen survival. Plant preparations such
as Eucalyptus oil [], babassu mesocarp extract [], and
oil from seeds of Chenopodium ambrosioides L. []were
found to activate the phagocytic activity of macrophages,
whereas essential oils from Petroselinum crispum [],
Artemisia iwayomogi [], and Jeju plant extract []were
found to suppress activity of splenocytes and macrophages,
indicating that the two oils may act through dierent mech-
anisms.
3.8. Benecial Eects on Gastrointestinal Microora. e
human intestinal tract hosts a vast population of diverse
bacterial communities that amount to as many as 12 cells
per g of fecal mass in an average human being [,].
e gut microbiota interacts with the host and inuences var-
ious biological processes [], including microbial defense
[]. With advances in high throughput sequencing and
metagenomics and development of gnotobiotic animals, the
abilitytoexplorethevariationsingutmicrobiotacompo-
sition and their eect on human health has signicantly
improved [,]. Modulations in dietary components
have been associated with uctuations in the composition
of gut microbial population and diversity [,], which
inturnaectshost’smetabolicfunctions[]andsuscep-
tibility to gastrointestinal bacterial infections []. David
and coworkers [] observed that short-term macronutrient
variation leads to a change in the gut microbial commu-
nity structure, with animal protein-based diet increasing
the abundance of bile-tolerant microorganisms (Alistipes,
Bilophila,andBacteroides)andreducingthelevelsofFir-
micutes that metabolize dietary plant polysaccharides (Rose-
buria,Eubacterium rectale,andRuminococcus bromii). Bailey
and group [] demonstrated that stress exposure disrupted
commensal microbial populations in the intestine of mice
and led to increased colonization of Citrobacter rodentium.
ese researchers in their subsequent study observed that
Lactobacillus reuteri attenuated the stress-enhanced severity
of C. rodentium infection in mice []. Interestingly, recent
studies have shown that PDAs that are highly bactericidal
towards enteric pathogens exert low antimicrobial eect
against commensal gut microbiota [,]. apa and
coworkers [] found that nerolidol, thymol, eugenol, and
geraniol inhibited growth of enteric pathogens such as E. coli
O:H, Clostridium dicile,andS. Enteritidis.Moreover,
the degree of inhibition was more on the pathogens than
thecommensalbacteria.SincePDAsandprobioticsexert
their antimicrobial eects by dierent mechanisms [], a
combinatorial approach using both could be more eective in
controlling pathogens as compared to using them separately.
However, research investigating their synergistic interactions
is scanty. Further research is necessary to comprehensively
elucidate the mechanism of action of such dietary interven-
tions and their eect on gut microbiota for designing eective
therapies that promote health by targeting diverse microbial
communities.
4. Challenges Associated with Using PDAs for
Pathogen Control
e ecacy of PDAs in controlling pathogens in the environ-
ment, high-risk foods, or their virulence in the host depends
on various intrinsic and extrinsic factors. Physiochemical
properties of PDAs such as solubility in aqueous solutions,
hydrophobicity, biodegradability, and stabilities are major
BioMed Research International
challenges that thwart their usage as natural biocontrol agents
in the environment [,]. In addition, factors such as
environmental temperature and atmospheric composition
also modulate their antimicrobial ecacy []. In food
products, the presence of fat [], carbohydrates [],
and proteins [] aects the ecacy of PDAs. Moreover,
chemical variability in PDAs, originating from dierences
in extraction protocols [,], aects the antimicrobial
ecacy [].AnotherconcernforPDAsistheirstrongaroma,
which may modulate the organoleptic property and taste
prole of food products. erefore, careful selection of PDAs
based on their chemical composition and eect on sensory
attributes of food product is warranted before recommending
their usage as food preservatives or direct oral supplements
for human consumption [].
5. Future Directions
With an increasing body of supporting literature, PDAs are
now recognized to play a critical role in the development of
eective therapeutics, either alone or in combination with
conventional antibiotics. However, the major challenges to
this include nding compounds with suciently lower MICs,
low toxicity, and high bioavailability for eective and safe use
in humans and animals.
Based on their modes of action, PDAs are classied
into three categories, including conventional antimicrobials,
multidrug resistance inhibitors, and compounds that target
specic or multiple virulence factors in microbes []. As
new approaches that target specic regulatory pathways and
bacterial virulence are becoming the paradigm of antibac-
terial therapeutics in recent years, characterization of the
mechanism of action of these compounds would pave the
way for the development of novel drugs that can circumvent
antimicrobial resistance and control infectious diseases.
Conflict of Interests
e authors declare that there is no conict of interests
regarding the publication of this paper.
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