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13 Addressing Antimicrobial Resistance by Repurposing Polyphenolic Phytochemicals with Novel Antibacterial Potential
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dihydrochalcones, aurones, anthocyanidins, proantocyanidins, biflavanoids, and neoflavonoids [39].
They are richly available in various plant pigments. The non-flavonoid class is divided into four differ-
ent subclasses: (1) phenolic acids, (2) stilbenes, (3) lignans, and (4) coumarins [41].
Phenolic acids are a dominant category under the non-flavonoid class of polyphenols and are
further subdivided into hydroxybenzoic acids (C1–C6 backbone) and hydroxycinnamic acids (C3–
C6 backbone), and structurally characterized by a carboxylic acid group linked to the phenolic ring
[42]. They generally exist in plants either in free form or esterified form. They also often exist as a
conjugate with a sugar moiety and proteins, and hydrolysable on acid or alkali treatment. Many
foods and beverages, such as wine, tea, coffee chocolate, vegetables, whole grains, and fruits, con-
tain hydroxycinnamic acid in very high concentrations [43].
Stilbenes are biosynthesized by plants during external influences such as infection or injury.
They contain a C6–C2–C6 backbone and structurally represent a 1,2-diphenylethylene nucleus
and exist either in the monomeric or oligomeric form. Resveratrol is a naturally occurring impor-
tant bioactive compound that falls under this category [41, 44].
Stilbenes, a coumarin type of polyphenol, also synthesize and accumulate in the plant tissues
because of abiotic stress and microbial attacks. Stilbenes comprise a 1,2-benzopyrone skeleton
(α-chromone) and they also frequently exist in prenylated form. Coumarin cores are often used as
a template in the synthesis of various pharmacologically important novel compounds [41, 45].
Lignans are a comparatively less abundant class of phenolic compounds structurally character-
ized by a dibenzylbutane skeleton. These types of compounds are generally found in higher plants
(gymnosperms, angiosperms, pteridophytes, etc.). Often, they are found in the plant material in
bound form and are difficult to extract [41, 45]. Table 13.3 depicts polyphenolic compounds,
including flavonoids and their dietary sources.
13.4.2 Chemistry of Plant Polyphenolics/ Flavonoids
In plant-derived polyphenolic compounds, flavonoids comprise the largest group with approxi-
mately 10,000 natural analogues. These are hydroxylated phenolic substances that are synthesized
by plants in response to microbial infection. They often exist as bright colored (yellow to red) pig-
ments in plants and microbes [49]. The structural framework of flavanoid compounds comprises a
benzo-γ-pyrone ring system (C6–C3–C6 backbone). Structurally, they are characterized as C15
compounds and comprise two phenolic (C6) rings that are linked by a bridge of heterocyclic pyrone
rings. Two phenolic rings are denoted as A and B rings, whereas, connecting heterocyclic rings are
considered as a C ring in the structural skeleton [41, 49]. The basic structural skeletons/backbones
of various types of flavonoids classes are represented in Figure 13.3.
The chemical nature and biological potential of flavonoids depends on their structural class,
degree of hydroxylation, other functional group substitutions, conjugations, and degree of polym-
erization that categorize them in different subclasses [50]. The different categories of flavonoids
varies in the degree of oxidation and arrangement of substitution of the C ring, while different
compounds within a class differ in the pattern of substitution of the A and B rings. Generally, the
B ring binds at Position 2 of the C ring; however, it can also be attached at Position 3 or 4. Ring B
can adopt different structural features and the three rings can undergo glycosylation and hydroxy-
lation [48]. Flavonoids generally contain three or more –OH groups that are linked to their struc-
tural skeleton and exert a wide array of structural configurations. Additionally, in nature they are
frequently found in glycosylated form with multiple sugar units, chemically termed as flavanoid
glycosides. Many of them are hydrolysable by acid treatment and the non-sugar part is called a
glycon [49, 51].
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13.4 Polyphenolic Phytochemicals as Antimicrobial Agents 269
Table 13.3 Classification of polyphenolic compounds/flavonoids and their dietary sources with examples
[43, 46–48].
Class Of
Polyphenols Subclass Prototype Compounds Major Dietary Sources
Flavonoids Flavone Baicalein, apigenin,
luteolin, chrysin
Herbal tea, fenugreek, onion,
garlic, pepper, citrus fruits,
green leafy vegetables
Isoflavone Genistein, daidzein,
biochanin A, glycitein
Chickpea, pea nut, dairy
products, egg, meat, seafood, soy
products, legumes
Flavonol Rutin, quercetin, myricetin,
fisetin
Tea, chocolate, cocoa, onions,
scallions, kale, broccoli, apples,
berries,
Flavanonol Taxifolin, aromadendrin,
engeletin
Milk thistle seeds, citrus fruits
Flavanol (−)- epicatechin,
(+)-catechin,
(−)-epigallocatechin gallate
(EGCG), theaflavins
Cocoa, chocolate, tea, grapes,
apples
Chalcone Butein, xanthoangelol,
4-hydroxyderricin,
cardamomin,
isoliquiritigenin,
isosalipurposide
Tomatoes, licorice, shallots, bean
sprouts
Flavanone Hesperidin, hesperetin,
naringin, naringenin,
eriodictyol
Pomegranate, citrus fruits,
tomatoes, grape fruit
Dihydrochalcones Phlorizin, aspalathin,
nothofagin
Apples and apple products,
rooibos tea
Anthocyanidins Cyanidin, peonidin,
delphinidin, petunidin,
pelargonidin, malvidin
Red wines, cherries, red grapes,
berries, flowers, oranges, black
soy beans, hibiscus sp., purple/
black rice, onions, red potatoes,
purple cabbage
Proantocyanidins Procyanidin B1,
procyanidin B2,
procyanidin B3
Berries, cherries, red grapes, red
wines, flowers, oranges, black
soy beans, banana, cocoa, and
apricot, cereals such as sorghum
and barley
Non-
flavonoids
Phenolic acids Caffeic acid, sinapic acid,
shikimic acid, gallic acid,
protocatechuic acid, ferulic
acid, p-coumaric acid,
Green tea, citrus fruits, kiwi,
coffee, berries, apples, rice bran,
passion fruit, cherries, mangoes,
wheat, corn flours
Stilbenes Resveratrol Grapes (skin), mulberries,
peanuts, red wine
Lignans Silymarin, sylibin, sesamin,
syringaresinol,
ecoisolariciresinol,
matairesinol, medioresinol,
pinoresinol, lariciresino
Flaxseed, soy beans, broccoli,
cabbage, milk thistle, apricots,
strawberries, etc.
Coumarins Dicumarol, osthole Cinnamon, green tea, carrot,
bison grass
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13 Addressing Antimicrobial Resistance by Repurposing Polyphenolic Phytochemicals with Novel Antibacterial Potential
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The flavanoid ring system (benzo-γ-pyrone ring), which contains a double bond between the C-2
and C-3 positions with a ketone group at C-4 of the C ring denoted as flavones, whereas, in fla-
vanones, the C ring is saturated containing a double bond between the C-2 and C-3 positions of the
ring. These are also called dihydroflavones [48, 50]. Flavonol has an additional OH group at the
C-3 position of the C ring, which makes them more polar than flavone and flavanones. Additionally,
they exist in dihydroflavonol form, which has a double bond between the C3–C4 positions.
Generally, glycosylation of flavonols occurs in the C-3 position of the C ring [41, 50]. Flavan-3-ols
or flavanols contain a hydroxyl group at the C-3 position of the C ring. Unlike other flavanoids,
isoflavonoids contain a B ring attached at the C-3 position of the C ring, whereas, in other flava-
noids, the B ring is attached at the C-4 position [51].
Anthocyanidins and anthocyanins are bright colored (blue, red, or purple pigments) flavanoid
compounds found in flowers, fruits, and leaves. These are positively charged compounds contain-
ing flavylium cations, and they often occur as chloride salts [41, 52]. Anthocyains comprise one or
more sugar moieties in the C-3 position of the C ring. Frequently, these compounds are found in
the plants as a conjugate with phenolic acids and other organic acids. The deglycosylated forms of
anthocyanins are called anthocyanidins. Variation in the color of the anthocyanin compounds is
reliant on the pH acylation and methylation of –OH groups attached to the A and B ring, and also
the pH of the environment [52].
Proanthocyanidins are the dimer or trimer of flavanols in condensed form, also known as con-
densed tannins. Based on the interflavanic linkages, they can be divided as type A (C2–O–C7 or
C2–O–C5 bonding) or type B (C4–C6 or C4–C8). They are often produced from flavanol-rich mate-
rials during fermentation [51]. Open C rings containing flavanoids are categorized as chalcones.
Chalcone compounds exert a common chemical scaffold of 1,3- diaryl-2-propen-1-one, which is
also known as a chalconoid [53]. Figure 13.4 represents the structures of plant-derived polyphe-
nolic compounds, including flavonoids.
Figure 13.3 Basic structural skeletons/backbones of flavonoids.
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Figure 13.4 Structures of plant-derived polyphenols and flavonoids.
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13 Addressing Antimicrobial Resistance by Repurposing Polyphenolic Phytochemicals with Novel Antibacterial Potential
272
13.4.3 Biological Importance and Antioxidant Potential of Flavonoids
Flavonoids are essential to plants for survival during infections, predator attacks, and environmen-
tal stresses such as drought. Colors of the different plant parts are dependent on the type of flavo-
noids present in the tissue. Flavonoids are also responsible for the plant’s communication with
insects and microbes as a chemical messenger [49].
Consumption of flavonoids is proven to have various potential therapeutic benefits against human
disease. A flavonoid-rich diet and supplements are attracting tremendous attention worldwide because
of their wide array of positive ameliorative roles in human disease and healthy aging [50]. Flavanoid-
rich herbal supplements are often found to be significantly effective in the management of hyperten-
sion, diabetes, and obesity, along with several other complications of metabolic syndromes. Additionally,
flavanoid-rich food also helps heal infections and wounds faster, and improve the immune system [47,
50, 51]. Scientific validations indicate that flavonoids have remarkable potential in the prevention and
management of several diseases. A variety of flavanoid molecules have a wide range of therapeutic
benefits including antioxidant, anticancer, antibacterial, antiviral, antifungal, hepatoprotective, cardio-
protective, antidiabetic, analgesic, and anti-inflammatory characteristics [47, 54].
Flavonoids exert excellent antioxidant effects by scavenging free radicals or chelating with metal
ions. These properties are because of the multiple hydroxyl groups (–OH) present in the structure
[55]. Flavonoids also activate the Nrf2-HO antioxidant pathway, which gives signals to produce
endogenous antioxidant enzymes to maintain the redox balance in the human body during various
OS conditions [56]. In addition to strong antioxidant properties, flavanoids also possess impressive
potential towards the protection of DNA damage and mitochondrial death [57]. The approximate
intake of 100 mg/day of total flavonoids in the daily diet may reduce the risk of all causes of mortal-
ity and cardiovascular disease by 6% and 4%, respectively [51]. Recent studies demonstrated that
polyphenols like flavonoids improve gut-microbial health and maintain healthy gastrointestinal
functions [58]. The free radical scavenging action of dietary flavonoids is displayed in Figure 13.5.
O
O
FI=O
O
O
O
O
OO
.
FI -O
FI-OH
OH
OH
OH
OH
OH
R
R H
.
R
R H
.
OH
OH
Figure 13.5 Free radical scavenging action of dietary flavonoids. Credit: JAVIER / Adobe Stock.
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13.4 Polyphenolic Phytochemicals as Antimicrobial Agents 273
13.4.4 Antimicrobial/Antibacterial Effectiveness of Flavonoids
Flavonoids exhibit a broad spectrum of antimicrobial actions through different mechanisms that
are often similar to those of conventional antibiotics and thus could be of importance in the aug-
mentation of antimicrobial therapeutics. The antimicrobial properties of various flavonoids, along
with their effectiveness against specific microbial strains and the mechanisms of action, are sum-
marized in Table 13.4.
The specific mechanisms of antimicrobial/antibacterial actions are discussed below:
1) Bacterial cell membrane disruption: The integrity of the bacteria plasma membrane is a
prerequisite for their essential cellular processes, including peptidoglycan biosynthesis,
osmoregulation, cellular respiration, transport processes, and crosslinking of peptidoglycan,
and therefore, the targeting of the bacteria cell membrane to interrupt the functions with chemi-
cal agents creates opportunities to kill them [61, 65]. A study shows that flavonoids can interact
with the polar and non-polar heads of a lipid bilayer of a bacterial cell membrane as they hold
Table 13.4 Flavonoids and their antibacterial activity with mechanisms of action [59–67].
Flavonoids Source
Bacterial Strain
Against which
They are Effective
Minimum
Inhibitory
Concentration
(MIC)
Mechanism(s) Of
Antibacterial
Action
Kaempferol
Maluspumila S. aureus
V. harveyi
20 μg/ml
6.25–100 μg/ml
Inhibition of
bacterial toxin;
Quorum sensing
inhibition
Quercetin Anthemis cotula S. aureus 50 μg/ml Inhibition of
bacterial toxin;
inhibition of
sortase
Vitexin Vitex negundo S. aureus 252 μg/ml Inhibition of
biofilm
formation;
Quorum sensing
inhibition
Farrerol Rhododendron
hainanense
S. aureus 0.5–8 μg/ml Quorum sensing
inhibition
Taxifolin Combretum
albiflorum
P. aeruginosa 4 mM Inhibition of cell
envelope
synthesis
Luteolin Cecropia
pachystachya
S. aureus 12.5–50 μg/ml Inhibition of
biofilm
formation;
Quorum sensing
inhibition
Chrysin Honey S. aureus 2–16 μg/ml Quorum sensing
inhibition
(Continued)
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Flavonoids Source
Bacterial Strain
Against which
They are Effective
Minimum
Inhibitory
Concentration
(MIC)
Mechanism(s) Of
Antibacterial
Action
Apigenin Citrus sinensis E. coli
S. mutans
V. harveyi
6.25–100 μg/ml
1.33 μg/ml
6.25–100 μg/ml
Inhibition of
biofilm
formation;
Quorum sensing
inhibition; Fatty
acid synthase
(FAS-II)
inhibition
Naringenin Bitter orange E. coli
V. harveyi
S aureus
P. aeruginosa
1–16 μg/ml
6.25–100 μg/ml
4
mM
Inhibition of
bacterial toxin;
Inhibition of
biofilm
formation;
Quorum sensing
inhibition;
Membrane
disruption
Naringin Bitter orange Y. enterocolitica 200 μg/ml Quorum sensing
inhibition
Hesperidin Bitter orange Y. enterocolitica 200 μg/ml Quorum sensing
inhibition
Dalbinol Amorpha
fruticosa
P. aeruginosa 6.25–25 μM Inhibition of
biofilm formation
Genistein Malusdo mestica E. coli 50 μg/ml Inhibition of
biofilm formation
Liquiritigenin Glycyrrhiza
glabra
S. aureus 4–32 μg/ml Quorum sensing
inhibition
Pinocembrin Apismellifera S. aureus 1–16 μg/ml Quorum sensing
inhibition
6,8-diprenyleriodictyol Dorstenia sp. S. aureus MSSA1 0.5 μg/ml Depolarization of
cell membrane;
inhibition of
DNA, RNA and
protein synthesis
Isobavachalcone Dorstenia sp. S. aureus MSSA1 2 μg/ml RNA and protein
synthesis
4-hydroxylonchocarpin Dorstenia sp. S. aureus MSSA1 16 μg/ml RNA and protein
synthesis
6-prenylapigenin Dorstenia sp. S. aureus MSSA1 4 μg/ml RNA and protein
synthesis
Glabrol Glycyrrhiza
glabra
MSSA
ATCC29213
MRSA T144
2 μg/ml Disruption of the
membrane
permeability
Table 13.4 (Continued)
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13.4 Polyphenolic Phytochemicals as Antimicrobial Agents 275
Flavonoids Source
Bacterial Strain
Against which
They are Effective
Minimum
Inhibitory
Concentration
(MIC)
Mechanism(s) Of
Antibacterial
Action
Licochalcone A Glycyrrhiza
glabra
MSSA
ATCC29213
MRSA T144
2–4 μg/ml ns
Licochalcone B Glycyrrhiza
glabra
MRSA T144 16 μg/ml ns
Licochalcone C Glycyrrhiza
glabra
MSSA
ATCC29213
MRSA T144
4 μg/ml ns
Licochalcone D Glycyrrhiza
glabra
MSSA
ATCC29213
MRSA T144
16–32 μg/ml ns
Licochalcone E Glycyrrhiza
glabra
MSSA
ATCC29213
MRSA T144
4 μg/ml ns
Glabrene Glycyrrhiza
glabra
MSSA
ATCC29213
MRSA T144
16 μg/ml ns
Licoisoflavone A Glycyrrhiza
glabra
MSSA
ATCC29213
MRSA T144
32 μg/ml ns
Licoflavone B Glycyrrhiza
glabra
MSSA
ATCC29213
MRSA T144
16–32 μg/ml ns
Licoflavone C Glycyrrhiza
glabra
MSSA
ATCC29213
MRSA T144
32–34 μg/ml ns
Puerarin Radix puerariae S. aureus 2–16 μg/ml Inhibition of
bacterial toxin
Silibinin Silybum
marianum
S. aureus 4–32 μg/ml Inhibition of
bacterial toxin
Baicalin Scutellaria
baicalensis
L. monocytogenes
P. aeruginosa
0.5–128 μg/ml
0.2–200 μM
Inhibition of
bacterial toxin;
Inhibition of
biofilm formation
Fisetin Hymenaea
courbaril
L. monocytogenes 0.88–28 μM Inhibition of
bacterial toxin;
FAS-I synthase
inhibitor
Morin Morus alba P. aeruginosa 750 μg/ml Inhibition of
bacterial toxin;
Coagulase
inhibitor;
Membrane
disruption; FAS-I
synthase
inhibitor
Table 13.4 (Continued)
(Continued)
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13 Addressing Antimicrobial Resistance by Repurposing Polyphenolic Phytochemicals with Novel Antibacterial Potential
276
Flavonoids Source
Bacterial Strain
Against which
They are Effective
Minimum
Inhibitory
Concentration
(MIC)
Mechanism(s) Of
Antibacterial
Action
6-Hydroxyflavone Barleria prionitis S. aureus 50 μg/ml Inhibition of
bacterial toxin
Myricetin Vitis vinifera Streptococcus
agalactiae
0.44–1.22
mM Inhibition of
bacterial toxin;
FAS-I synthase
inhibitor
Negletein Scutellaria
oblonga
S. aureus 32 μg/ml Inhibition of
biofilm formation
8-prenylnaringenin Humulus lupulus S. aureus 100 μg/ml Inhibition of
biofilm formation
Alopecurone A, D Saphora
alopecuroides
S. epidermidis 1.56–100 μg/ml Inhibition of
biofilm formation
Neoeriocitrin Citrus bergamia V. harveyi 6.25–100 μg/ml Inhibition of
biofilm formation
Neohesperidin Bitter orange Y. enterocolitica 200 μg/ml Inhibition of
biofilm
formation;
Quorum sensing
inhibition
Kaempferol-3-rutinoside Saphora japanica S. mutans 60.7 μg/ml Sortase enzyme
inhibition
Kurarinol Saphora
flavescens
S. aureus 25–100 μg/ml Sortase enzyme
inhibition
Quercitrin Rhus verniciflua S. mutans 16–256 μg/ml Sortase enzyme
inhibition
Baicalein Scutellaria
baicalensis
P. aeruginosa
H. pylori
0.2–200 μM
0.42–1
mM
Inhibition of
biofilm
formation;
Urease inhibitor
Genistein Malusdo mestica E. coli 50 μg/ml Inhibition of
biofilm formation
Dalbinol Amorpha
fruticosa
P. aeruginosa 6.25–25 μM Inhibition of
biofilm formation
Amoradicin, amoricin,
amorisin, isoamoritin
Amorpha
fructosa
C. perfringens 1–100 μM Neuraminidase
inhibitor
Auriculasin, flemingsin,
flemiphilippinin E
Flemingia
philippinensis
C. perfringens 0.05–80 μg/ml Neuraminidase
inhibitor
Erysubin E,
neorautenol, phaseollin,
cristacarpin
Erythrina
abyssinica
C. perfringens
V. cholerae
0.1–100 μM Neuraminidase
inhibitor
Sulfuretin Dalbergia
odorifera
R. solanacearum 50 mg/mL ns
Hematoxylin Haematoxylon
brasiletto
S. aureus 4.57 mM ns
Table 13.4 (Continued)
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13.4 Polyphenolic Phytochemicals as Antimicrobial Agents 277
Flavonoids Source
Bacterial Strain
Against which
They are Effective
Minimum
Inhibitory
Concentration
(MIC)
Mechanism(s) Of
Antibacterial
Action
Brazilin Haematoxylon
brasiletto
S. aureus 4.83 mM ns
Isolupalbigenin Erythrina
poeppigiana
MRSA 1.56–3.13 μg/ml ns
Lupiwighteone Ficustikoua Bur. P. infestans 90.365 μg/ml ns
Formononetin Dalbergia
frutescens
G. lamblia 0.03–0.01 μg/ml ns
Biochanin A Cassia fistula T. cruzi 18.32 μg/ml ns
Daidzein Apple fruit C. violaceum 50–200 μg/ml ns
Flemiphilippinin A Flemingia
philippinensis
C. perfringens 0.05–80 μg/ml ns
Erythribyssin L Erythrina
abyssinica
C. perfringens
V. cholera
0.1–100 μM ns
Conrauiflavonol Ficus conraui E. coli 64 μg/ml ns
Quercetin 3-O-methyl
ether
Cistus laurifolius H. pylori 3.9 μg/ml ns
Ericoside Erica mannii E. coli 64 μg/ml ns
3-O-methyldiplacol Paulownia
tomentosa
S. aureus 2.4 μg/ml ns
Taxifolin-7-O-α-l-
rhamnopyranoside
Hypericum
japonicum
S. aureus 32 μg/ml ns
Dihydrokaempferol Commiphora
pedunculata
S. aureus 625 μg/ml ns
Sepicanin A Artocarpus
sepicanus
MRSA 2.9 μM ns
Mimulone Paulownia
tomentosa
S. aureus 4.9 μM ns
Sophoraflavanone G Sophora
alopecuroides
S. epidermidis 3.1–12.5 μg/ml ns
Ochnaflavone Ochna
pretoriensis
P. aeruginosa 31.3 μg/ml ns
Lupinifolin Mundulea sericea S. aureus 0.5 μg/ml ns
Pinocembrin Cryptocarya
chinensis
M. tuberculosis 3.5 μg/ml ns
Kurarinol Sophora
flavescens
S. aureus 107.7 μM ns
Quercetin
3-O-β-D-rutinoside
Marrubium
globosum
P. vulgaris 320 μg/ml ns
Piliostigmol Piliostigma
reticulatum
E. coli 2.57 μg/ml ns
Elatoside A, B Epimedium
elatum
S. typhi 20 mM ns
Table 13.4 (Continued)
(Continued)
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