Mechanism of Action and Potential for Use of Tea Catechin as an Antiinfective Agent

Anti-Infective Agents in Medicinal Chemistry, 2007, 6, 57-62
57
Mechanism of Action and Potential for Use of Tea Catechin as an Anti-
infective Agent
Tadakatsu Shimamura1,* Wei-Hua Zhao2 and Zhi-Qing Hu1
1Department of Microbiology and Immunology; 2Department of Medical Biology, Showa University School of Medicine,
Tokyo, Japan
Abstract: “Drinking several cups of green tea a day keeps the doctor away” is clearly an overstatement. However, exten-
sive research has revealed that the predominant catechin from tea (Camellia sinensis), epigallocatechin gallate (EGCg),
has significant medicinal and health-promoting properties. This review summarizes what is presently known about the
antimicrobial properties of EGCg, with a particular focus on the synergistic relationship between EGCg and ?-lactams in
the inhibition of methicillin-resistant Staphylococcus aureus (MRSA). The mechanisms of action and prospects for use of
tea catechins such as EGCg as an anti-infective agent are discussed.
Keywords: Tea, catechins, EGCg, polyphenols, flavanols, antimicrobial agents, ?-lactams, MRSA.
INTRODUCTION
lactams against methicillin-resistant Staphylococcus aureus
(MRSA). The mechanisms of action and prospects for use of

Clinical reports indicate that antibiotic resistance in bac-
tea catechin as an anti-infective agent are discussed.
terial pathogens is an escalating problem. Antimicrobial
agents from natural products and traditional medicines could
serve as viable supplements to the present range of antibiot-
DIFFERENT SUSCEPTIBILITIES OF
STAPHY-
ics. Tea (Camellia sinensis) is one of the most popular bev-
LOCOCCUS AND GRAM-NEGATIVE RODS TO
erages worldwide. In traditional Chinese medicine, tea was
EGCG
AND
THE
MECHANISM
OF
ANTI-
regarded as a panacea, with antipyretic, antidotal, antidiar-
BACTERIAL ACTIVITY OF CATECHINS
rhoeal, and diuretic properties, indicating an anti-infective

In the 1990s, research focused on determining the anti-
activity with our modern concept. However, until the end of
bacterial activity and species specificity of individual cate-
the 1980s, there were limited reports and experimental data
chins. EGCg and ECg are the most potent catechins showing
describing the antimicrobial properties of tea [1,2].
antibacterial activity [1,2]. The activity of these two cate-

The beneficial effects of tea are attributable to catechins
chins may be attributable to the galloyl moiety, which is ab-
and their derivatives, which account for 30% of the dry
sent from EC and EGC (Fig. 1). The antibacterial activity of
weight of the water-extractable material from tea [3]. In
catechins was regarded as non-specific with limited species
1985, Matsuzaki and Hara successfully extracted catechins
selectivity. Further research revealed that Staphylococcus
from green tea, enabling further mechanistic characterization
and Gram-negative rods such as Escherichia coli (E. coli)
of this class of compounds [4]. Fig. (1) shows the chemical
show different susceptibilities to EGCg [2,11], with the
structures of catechins including (+)-catechin (molecular
minimum inhibitory concentrations (MICs) of 50-100 µg/ml
weight, MW 290) and the isomers (?)-epicatechin (EC, MW
and > 800 µg/ml, respectively. Also, more EGCg binds to
290), (?)-epigallocatechin (EGC, MW 306), (?)-epicatechin
Staphylococcus aureus (S. aureus) than E. coli, specifically,
gallate (ECg, MW 442), and (?)-epigallocatechin gallate
38% of EGCg at 50 µg/ml binds to live S. aureus, but only
(EGCg, MW 458). The polyphenol or flavanol moiety is
18% to E. coli [11]. EGCg-treated S. aureus was more sensi-
common to all catechins.
tive to high ionic strength and low osmotic pressure [12].
These data indicated that cell wall composition was a deter-

EGCg is the major catechin in green tea, where it ac-
minant for EGCg binding and activity. In order to verify this,
counts for about 50 to 65% of total catechins as reviewed by
peptidoglycan, lipopolysaccharide (LPS) and dextran were
Zaveri [5] and Nagle et al. [6]. Extensive research has re-
added to S. aureus cultures grown in the presence of EGCg.
vealed that EGCg possesses a range of biological and me-
As summarized in (Fig. 2), peptidoglycan, LPS or dextran
dicinal properties, including antioxidant [7], anti-carcinogen
alone showed no effect on bacterial growth, however, pepti-
[8,9], anti-obesity [10], antibacterial, antiviral and anti-
doglycan blocked the bactericidal activity of EGCg whereas
enzymatic effects [1,2,5]. This review focuses on recent find-
LPS and dextran did not [11,12].
ings about the antimicrobial activity of EGCg, particularly
the synergistic effect of EGCg in combination with ?-

Peptidoglycan is a cross-linked complex of polysaccha-

rides and peptides. The cell wall of Staphylococcus is com-
posed of 30-50 layers of peptidoglycan where it provides
*Address correspondence to this author at the Department of Microbiology
and Immunology, Showa University School of Medicine, 1-5-8 Hatanodai,
osmotic protection, aids in cell division and serves as a
Shinagawa-ku, Tokyo 142-8555, Japan; Tel: +81-3-3784-8131; Fax: +81-3-
primer for further biosynthesis of peptidoglycan [13]. EGCg
3784-3069; E-mail: saikin@med.showa-u.ac.jp
can directly bind to peptidoglycan and induce its precipita-

1871-5214/07 $50.00+.00
© 2007 Bentham Science Publishers Ltd.

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58 Anti-Infective Agents in Medicinal Chemistry, 2007, Vol. 6, No. 1
Shimamura et al.
tion (unpublished result). Therefore, the EGCg-induced
tant permeability barrier which provides protection against
damage of the cell wall and interference with its biosynthesis
various antibacterial materials [14]. Hence, the physiological
through direct binding with peptidoglycan are the major rea-
function of the outer membrane and the low affinity between
sons for the susceptibility of Staphylococcus to EGCg.
EGCg and LPS limit the binding of EGCg to peptidoglycan,

thereby reducing the susceptibility of Gram-negative rods to
OH
EGCg.

OH


HO

O



OH


OH


(+) catechin


OH


OH


HO
O




OH


OH


(-) epicatechin (EC)


OH


OH


HO
O

OH



OH


OH
Fig. (2) . Antagonism of the bactericidal activity of EGCg by pepti-

(-) epigallocatechin (EGC)
doglycan (PGN). S. aureus cells (5 x 105/ml) were inoculated in

Mueller-Hinton broth containing 100
OH
µg/ml EGCg, 512 µg/ml
PGN, 512 µg/ml LPS or 2048 µg/ml dextran and then cultured at

OH
37ºC for 24 hours. The bacterial cultures were sampled and serially

diluted to spread on Mueller-Hinton agar plates for an additional 24
HO
O
OH
h cultures. The colony forming units/ml (CFU/ml) of bacterial cul-

tures were calculated.

O C
OH

To elucidate whether peptidoglycan specifically blocks

OH
O
the activity of EGCg, fetal calf serum, peptone or dextran
OH

were added to cultures of S. aureus containing EGCg. Pep-
(-) epicatechin gallate (ECg)

tone, fetal calf serum and dextran alone did not affect bacte-
rial growth. However, a combination of fetal calf serum or
OH

peptone appeared to interfere with the activity of EGCg. In-
OH

dividual or combined amino acids did not affect the activity
of EGCg [11]. These results suggest that components of fetal

HO
O
OH
calf serum and peptone bind to EGCg and block its activity.
OH

Catechins are polyphenols and components of condensed
O C
OH
tannins [15], which can precipitate proteins by direct binding

[15,16]. This property of catechins is mainly responsible for
OH
O

the antibacterial activity but makes EGCg be non-specific
OH
and low bioavailable in vivo.

(-) epigallocatechin gallate (EGCg)

Following the observation that EGCg damages
Fig. (1). Chemical structure of catechins.
liposomes, Ikigai et al. hypothesized that EGCg attacks the
lipid bilayer of bacterial cell membranes in a similar fashion

Although Gram-negative rods have several layers of the
[17]. However, this activity may be minor since the bacterial
peptidoglycan, they are overlaid with an outer membrane
cell membrane is protected by an outer cell wall. In phos-
composed mainly of LPS. The outer membrane is an impor-
phate buffered saline (PBS) at neutral pH, EGCg generates

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Mechanism of Action and Potential for Use of Tea Catechin
Anti-Infective Agents in Medicinal Chemistry, 2007, Vol. 6, No. 1 59
hydrogen peroxide (H2O2) which is responsible for bacteri-
and increases the susceptibility of Staphylococcal isolates to
cidal action of EGCg in PBS [18]. However, this phenome-
tetracycline [33].
non can not be confirmed in Mueller-Hinton broth, the stan-

EGCg has antagonistic effects on the antibacterial activi-
dard medium for antibacterial assay (unpublished result).
ties of the glycopeptide antibiotics, vancomycin, teicoplanin
Further research is required to determine the involvement of
and polymyxin B. EGCg binds to the peptide backbones of
EGCg-derived H2O2 in the bactericidal action.
these antibiotics and impairs their activity [27].
EFFECTS OF EGCG IN COMBINATION WITH
MECHANISMS
OF
ANTIVIRAL
AND
ANTI-
ANTIBIOTICS AGAINST MULTIDRUG-RESISTANT
ENZYMATIC ACTIVITIES OF CATECHINS
BACTERIA

The effects of tea and tea catechins on viruses, and vari-

MRSA is a major nosocomial pathogen which expresses
ous enzymes derived from bacteria, viruses and cells have
penicillin binding protein 2’ (PBP2’) with reduced affinity
also been studied. Antiviral activities have been observed
for ?-lactam rings. Therapeutic options for treating MRSA
against tobacco mosaic virus [34], influenza virus [35-42],
infections are limited because most MRSA strains are also
rotavirus [43], enterovirus [43], HIV [44-47], herpes simplex
resistant to macrolides, aminoglycosides, and fluoroqui-
virus [48,49], adenovirus [50], and Epstein-Barr virus
nolones [19]. Isolates with reduced sensitivity to vancomycin
[51,52]. The 50% inhibition concentrations (IC
have also been detected [20]. New chemotherapeutic agents
50) of EGCg,
ECg, and EGC, for example, against influenza A virus are
are urgently needed to control such multidrug-resistant bac-
10.1-12.8, 9.7-17.7 and 94.6-97.3 µg/ml, respectively [41].
teria. EGCg is an excellent candidate, as extensive research
Anti-enzymatic activities of catechins have been observed
has revealed that ?-lactams and EGCg have synergic effects
against ?-lactamases [31,32], reverse transcriptase of HIV
against multidrug-resistant bacteria [12,21-29]. As shown in
[53,54], collagenase [55], fatty acid synthase [56], and vari-
(Fig. 3), EGCg dose-dependently reverses the high level re-
ous other enzymes [57-62]. We observed that EGCg inhibits
sistance of clinical isolates of MRSA to ?-lactams. EGCg
penicillinase in a dose-dependent fashion, with an IC
synergizes the activity of ?-lactams against MRSA because
50 of 10
µg/ml versus 10 U/ml of the enzyme [31]. EGCg inhibits
both EGCg and ?-lactams directly or indirectly attack the
viruses and enzymes by direct binding to biological mole-
same target: peptidoglycan synthesis [12]. However, the pos-
cules [31,32,37,54-62]. EGCg induces agglutination of the
sibility that EGCg binds with PBP2’ and then inhibits its
influenza virus thus preventing their adsorption to target
enzymatic activity cannot be excluded.
cells [37]. In addition, the direct binding of EGCg to viral

The most common resistance mechanism to ?-lactams is
receptors on cell surfaces may also interfere with viral infec-
?-lactamase production. Penicillinase occurred in less than
tivity, following the observation that EGCg binds to CD4
5% of S. aureus isolates at the time of penicillin’s introduc-
and interferes with binding by the HIV surface protein,
tion into clinics in the 1940s, but has dramatically increased
gp120 [46].
to 80-90% of isolates at the present time [30]. The combined
effects of EGCg and ?-lactams have been examined in vari-
PROSPECT FOR USE OF TEA CATECHIN AS AN
ous ?-lactamase-producing clinical isolates. The combina-
ANTI-INFECTIVE AGENT
tion of EGCg with penicillin shows potent synergy against
penicillinase-producing S. aureus [31]. Direct binding of

The synergistic effects of EGCg and ?-lactams against
EGCg with penicillinase inhibits enzymatic activity and pro-
MRSA and penicillinase-producing S. aureus, and the potent
tects the antibacterial activity of penicillin. A synergic effect
anti-viral activity of EGCg suggest tea catechins may be
was not observed when cefotaxime or imipenem were com-
valuable therapeutics. However, to date, studies of the anti-
bined with EGCg (100 µg/ml) to inhibit ?-lactamase-
bacterial, antiviral and anti-enzymatic properties of catechins
producing Gram-negative rods, even though EGCg directly
have been restricted to in vitro settings. Furthermore, the
blocked the activity of the ?-lactamase extracted from these
inhibitory activities are non-specific. EGCg inhibits the re-
bacteria [32]. The combined effects on different ?-
verse transcriptase of HIV only in the absence of serum al-
lactamase-producing species appear dependant on the cellu-
bumin [54] and the antibacterial activities of EGCg are
lar location of ?-lactamase [32]. Staphylococcal ?-lactamase
strongly affected by the presence of proteins in the culture
is extracellular, whereas the ?-lactamases of Gram-negative
medium [11]. It is likely, therefore, that under in vivo condi-
rods are located in the periplasm.
tions, serum proteins and other biological macromolecules
may strongly affect the bioavailability of catechins

The effects of combining EGCg and non-?-lactam anti-
[11,15,16,54] and some of the antimicrobial effects observed
biotics have also been studied. Table 1 summarizes the syn-
in vitro may not occur in vivo.
ergic, additive, indifferent and antagonistic effects observed
in vitro when different antibiotics are combined with EGCg

Drinking tea or taking EGCg capsules is the only safe
against MRSA [12,26,27].
way to administer EGCg in humans. It is difficult to estimate
the in vivo concentration of EGCg following its absorption

Additive or indifferent effects on MRSA were observed
through the digestive system and distribution to various or-
when EGCg was combined with inhibitors of protein or nu-
gans, especially given its propensity to bind with serum or
cleic acid synthesis [27]. Increased permeability of the cell
tissue proteins. EGCg of 5.6 µg/ml was detected in rat blood
wall/membrane to antibiotics following EGCg-induced dam-
plasma following administration at 500 mg/kg body weight
age of the cell wall may explain the additive effects. It is also
[63]. In a similar study, EGCg of 2 µg/ml was detected in
reported that EGCg can impair the tetracycline-specific ef-
human blood plasma 90 minutes after administration of a
flux pump, which raises the intracellular drug concentration
525 mg EGCg capsule [64]. These concentrations are not

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60 Anti-Infective Agents in Medicinal Chemistry, 2007, Vol. 6, No. 1
Shimamura et al.








































Fig. (3). Synergistic effects between EGCg and ?-lactams against MRSA. MRSA cells (5 x 105/ml) were inoculated in Mueller-Hinton broth
containing different concentrations of EGCg and various ?-lactams, and then cultured at 37ºC for 24 hours. Bacterial growth was examined
using a spectrophotometer. ?: ?-lactam alone; ?: ?-lactam plus 6.25 µg/ml EGCg; ??: ?-lactam plus 12.5 µg/ml EGCg; ?: ?-lactam plus 25
µg/ml EGCg.

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Mechanism of Action and Potential for Use of Tea Catechin
Anti-Infective Agents in Medicinal Chemistry, 2007, Vol. 6, No. 1 61
Table 1. Effects of EGCg in Combination with Various Antibiotics on MRSA
EGCg + Antibiotic*
Synergy
Addition
Indifference
Antagonism
?-Lactams
+
-
-
-
Inhibitors of protein synthesis
-
±
±
-
Inhibitors of nucleic acid synthesis
-
±
±
-
Glycopeptides
-
-
-
+
* Tested antibiotics. ?-Lactams: penicillin, ampicillin, methicillin, oxacillin, cephalexin, cefmetazol, cefotaxime, imipenem, panipenem, meropenem; Inhibitors of protein synthesis:
tetracycline, minocycline, chloramphenical, streptomycin, gentamicin, kanamycin, erythromycin; Inhibitors of nucleic acid synthesis: ofloxacin, rifampicin; Glycopeptides: vancomy-
cin, teicoplanin, polymyxin B.
high enough to exert antimicrobial activity. It is plausible
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EGCg = Epigallocatechin gallate
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Received: August 25, 2006
Revised: September 22, 2006
Accepted: September 23, 2006

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