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Antimicrobial activity of flavonoids

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Cushnie TPT, Lamb AJ. Antimicrobial activity of flavonoids. International Journal of

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 Review Antimicrobial activity of flavonoids
∗
T.P. Tim Cushnie, Andrew J. Lamb
School of Pharmacy, The Robert Gordon University, Schoolhill, Aberdeen AB10 1FR, UK

Abstract

Flavonoids are ubiquitous in photosynthesising cells and are commonly found in fruit, vegetables, nuts, seeds, stems, flowers, tea,
wine, propolis and honey. For centuries, preparations containing these compounds as the principal physiologically active
constituents have been used to treat human diseases. Increasingly, this class of natural products is becoming the subject of
anti-infective research, and many groups have isolated and identified the structures of flavonoids possessing antifungal, antiviral
and antibacterial activity. Moreover, several groups have demonstrated synergy between active flavonoids as well as between
flavonoids and existing chemotherapeutics. Reports of activity in the field of antibacterial flavonoid research are widely
conflicting, probably owing to inter- and intra-assay variation in susceptibility testing. However, several high-quality
investigations have examined the relationship between flavonoid structure and antibacterial activity and these are in close
agreement. In addition, numerous research groups have sought to elucidate the antibacterial mechanisms of action of selected
flavonoids. The activity of quercetin, for example, has been at least partially attributed to inhibition of DNA gyrase. It has also
been proposed that sophoraflavone G and (−)-epigallocatechin gallate inhibit cytoplasmic membrane function, and that
licochalcones A and C inhibit energy metabolism. Other flavonoids whose mechanisms of action have been investigated include
robinetin, myricetin, apigenin, rutin, galangin, 2,4,2 -trihydroxy-5 -methylchalcone and lonchocarpol A. These compounds
represent novel leads, and future studies may allow the development of a pharmacologically acceptable antimicrobial agent or
class of agents. © 2005 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Keywords: Flavonoids; Antifungal; Antiviral; Antibacterial; Structure–activity; Mechanism of action

262 555.
E-mail address: [email protected] (A.J. Lamb).
including ß-lactams and quinolones [5]. It is not
1. Introduction surprising then, that in response to antimicrobial
resistance, major phar- maceutical companies have
Resistance to antimicrobial agents has become an tended to concentrate their efforts on improving
increas- ingly important and pressing global antimicrobial agents in established classes [6].
problem. Of the 2 million people who acquire However, with the portfolio of chemotherapeutics
bacterial infections in US hospitals each year, 70% of currently available, it has been acknowledged that
cases now involve strains that are resistant to at least researchers are get- ting close to the end game in
one drug [1]. A major cause for concern in the UK is terms of parent structure alter- ations. A call has
methicillin-resistant Staphylococcus aureus (MRSA), therefore been made for the development of new
which was at low levels a decade ago but now classes of drug that work on different target sites to
accounts for ca. 50% of allS. aureus isolates [2]. those in current use [7,8].
Substantial investment and research in the field of Rational drug design does not always yield effective
anti-infectives are now desperately needed if a public antimicrobials. In the past, potent enzyme inhibitors
health crisis is to be averted. have been successfully designed and synthesised but
Structural modification of antimicrobial drugs to they had only modest antibacterial activity, probably
which resistance has developed has proven to be an owing to the com- plex issue of drug uptake by cells.
effective means of extending the lifespan of Broad empirical screen- ing of chemical entities for
antifungal agents such as the azoles [3], antiviral antimicrobial activity represents an alternative
agents such as the non-nucleoside reverse strategy for the development of novel drugs. Natural
transcriptase inhibitors [4], and various antibacterial products have been a particularly rich source of
agents anti-infective agents, yielding, for example, the
penicillins in 1940, the tetracyclines in 1948 and the
glycopeptides in
∗ Corresponding author. Tel.: +44 1224 262 526; fax: +44 1224

0924-8579/$ – see front matter © 2005 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
doi:10.1016/j.ijantimicag.2005.09.002
International Journal of Antimicrobial Agents 26 (2005) 343–356
344 T.P.T. Cushnie, A.J. Lamb / International Journal of Antimicrobial Agents 26 (2005) 343–356
preparations [14]. The function of flavonoids in
1955 [9]. The following review will examine the flowers is to provide colours attractive to plant
antimi- crobial activity of flavonoids, a class of pollinators [11,15]. In leaves, these com- pounds are
natural products possessing a diverse range of increasingly believed to promote physiologi- cal
pharmacological properties. Compounds with survival of the plant, protecting it from, for example,
antifungal, antiviral and antibacterial activ- ity will fungal pathogens and UV-B radiation [13,15]. In
each be discussed in turn, with particular emphasis addition, flavonoids are involved in
on those flavonoids with antibacterial activity. photosensitisation, energy transfer, the actions of
plant growth hormones and growth regulators,
control of respiration and photosynthesis,
2. Flavonoids: occurrence, functions, structure morphogenesis and sex determination [11,13].
and nomenclature The basic structural feature of flavonoid compounds
is the 2-phenyl-benzo[α]pyrane or flavane nucleus,
Flavonoids are ubiquitous in photosynthesising cells which consists of two benzene rings (A and B)
and therefore occur widely in the plant kingdom linked through a heterocyclic pyrane ring (C) (Fig. 1)
[10]. They are found in fruit, vegetables, nuts, seeds, [16]. Flavonoids can be classified according to
stems and flowers as well as tea, wine [11], propolis biosynthetic origin. Some classes, for exam- ple
and honey [12], and represent a common constituent chalcones, flavanones, flavan-3-ols and
of the human diet [13]. In the US, the daily dietary flavan-3,4-diols, are both intermediates in
intake of mixed flavonoids is estimated to be in the biosynthesis as well as end prod- ucts that can
range 500–1000 mg, but this figure can be as high as accumulate in plant tissues. Other classes are only
several grams for people supplementing their diets known as end products of biosynthesis, for example
with flavonoids or flavonoid-containing herbal anthocyanidins, proanthocyanidins, flavones and
flavonols. Two additional classes of flavonoid are
those in which the 2-phenyl side chain of flavanone Increasingly, flavonoids are becoming the subject of
isomerises to the 3 posi- tion, giving rise to medi- cal research. They have been reported to
isoflavones and related isoflavonoids. The possess many useful properties, including
anti-inflammatory activity, oestrogenic activity,
enzyme inhibition, antimicrobial activity [10,13],
antiallergic activity, antioxidant activity [11],
vascular activ- ity and cytotoxic antitumour activity
[15]. For a group of compounds of relatively
homogeneous structure, the flavonoids inhibit a
perplexing number and variety of eukary- otic
enzymes and have a tremendously wide range of
activi- ties. In the case of enzyme inhibition, this has
been postulated to be due to the interaction of
enzymes with different parts of the flavonoid
Fig. 1. The skeleton structure of the flavones (a class of molecule, e.g. carbohydrate, phenyl ring, phe- nol
flavonoids), with rings named and positions numbered [13].
and benzopyrone ring [10]. Several reviews have
neoflavonoid is formed through further isomerisation been written on the interaction between flavonoids
to the 4 position [13]. Structures of the major classes and mammalian cells, including comprehensive
of flavonoids are given in Fig. 2. The structures of articles by Harborne and Williams [15] and
specific compounds within these classes that possess Middleton et al. [20]. An extensive review on the
antimicrobial activity and that are discussed in the biochemistry and medical significance of flavonoids
present review are summarised in Table 1. has also recently been produced by Havsteen [21].
Individual flavonoids may be assigned names in
three dif- ferent ways. Trivial names are employed
extensively and sometimes indicate flavonoid class 4. History of flavonoid use in antimicrobial
or plant source. For exam- ple, names ending in treatment
‘inidin’ can denote an anthocyanidin, names ending
in ‘etin’ generally denote a flavonol, and compounds For centuries, preparations that contain flavonoids as
tricin and hypolaetin have been extracted from plants the principal physiologically active constituents have
belonging to the genera Triticum and Hypolaena. been used by physicians and lay healers in attempts
Flavonoids may also be named in a semi-systematic to treat human diseases [10]. For example, the
man- ner based on trivial names such as flavone or plantTagetes minuta(contain- ing
chalcone as the parent structure, e.g. 3,5,7,3 4 quercetagetin-7-arabinosyl-galactoside) has been
-pentahydroxyflavone or 3,3 ,4 used extensively in Argentine folk medicine to treat
,5,7-pentahydroxyflavone. Lastly, flavonoids may be infectious dis- ease [22]. The healing properties of
given systematic chemical names, e.g. propolis (or ‘tzori’ in Hebrew) are referred to
3,4-dihydro-2-phenyl- 2H-1-benzopyran for flavan, throughout the Old Testament [23], and this balm
but this method is cumbersome and rarely used [13]. was prescribed by Hippocrates (460–377 BC) in
In the present review, trivial names will be used Ancient Greece for the treatment of sores and ulcers
wherever possible. [24].

3. Medicinal properties of flavonoids

flavones [10], flavonols [10], flavanon-3-ols [13], anthocyanidins [13,20], flavan-3-ols [10,13], proanthocyanidins (occur as dimers, trimers,
tetramers and pentamers; R = 0, 1, 2 or 3 flavan-3-ol structures) [13], flavans [13], flavan-3,4-diols [13] and dihydrochalcones [13].
T.P.T. Cushnie, A.J. Lamb / International Journal of Antimicrobial Agents 26 (2005) 343–356 345
346 T.P.T. Cushnie, A.J. Lamb / International Journal of Antimicrobial Agents 26 (2005) 343–356
Table 1 A summary of the structures of antimicrobial flavonoids discussed within the present review article (compiled from The Handbook of
Natural Flavonoids [13] and individual research papers)
Compound Substituents at carbon position:
234567823456
Flavones and their glycosides

Acacetin – – – OH – OH – – – OCH3 – – Apigenin – – – OH – OH – – – OH – – Baicalin – – – OH OH OR1 – – – – – – Baicalein – – – OH OH

OH – – – – – – Chrysin – – – OH – OH – – – – – – Gardenin A (demethylated) – – – OH OH OH OH – OH OH OH – Genkwanin – – – OH –

OCH3 – – – OH – – Luteolin – – – OH – OH – – OH OH – – Luteolin 7-glucoside – – – OH – OR2 – – OH OH – – 7,8-Dihydroxyflavone – – – –

– OH OH – – – – – 5,5 -Dihydroxy-8,2 ,4 -trimethoxyflavone – – – OH – – OCH3 OCH3 – OCH3 OH – 5-Hydroxy-7,4 -dimethoxyflavone – – –

OH – OCH3 – – – OCH3 – – 5,7,4 -Trihydroxy-3 ,5 -dimethoxyflavone – – – OH – OH – – CH3 OH CH3 – 6,7,4 -Trihydroxy-3 ,5

-dimethoxyflavone – – – – OH OH – – CH3 OH CH3 –
Isoflavones
6,8-Diprenylgenistein – – – OH R3 OH R3 – – OH – – Sophoraisoflavone A – – – OH – OH – * * OH – –
Flavonols and their glycosides

Galangin – OH – OH – OH – – – – – – Kaempherol – OH – OH – OH – – – OH – – 3-O-methylquercetin – OCH3 – OH – OH – – OH OH – –

Morin – OH – – – OH – OH – OH OH – Myricetin – OH – OH – OH – – OH OH OH – Quercetagetin – OH – OH OH OH – – OH OH – –
Quercetagetin-7-arabinosyl-galactoside – OH – OH OH OR4 – – OH OH – – Quercetin – OH – OH – OH – – OH OH – – Quercetin-3-O-(2
-galloyl)-α-L- arabinopyranoside
– OR5 – OH – OH – – OH OH – –
Quercetrin – OR6 – OH – OH – – OH OH – – Robinetin – OH – – – OH – – OH OH OH – Rutin – OR7 – OH – OH – – OH OH – – 3,2
-Dihydroxyflavone – OH – – – – – OH – – – – 3,6,7,3 ,4 -Pentahydroxyflavone – OH – – OH OH – – OH OH – –
Flavan-3-ols
Catechin – OH OH – – OH – – OH – OH – Epicatechin gallate – R8 – OH – OH – – OH OH – – Epigallocatechin – OH – OH – OH – – OH OH
OH – Epigallocatechin gallate – R8 – OH – OH – – OH OH OH – 3-O-octanoyl-(+)-catechin – R9 – OH – OH – – OH OH – –
3-O-octanoyl-(−)-epicatechin – R9 – OH – OH – – OH OH – –
Flavanon-3-ols
Dihydrofisetin – OH – – – OH – – OH OH – – Dihydroquercetin – OH – OH – OH – – OH OH – –
Flavanones and their glycosides
Lonchocarpol A – – – OH R3 OH R3 – – OH – – Naringenin – – – OH – OH – – – OH – – Naringin – – – OH – OR7 – – – OH – – Pinocembrin –

– – OH – OH – – – – – – Ponciretin – – – OH – OH – – – OCH3 – – Sophoraflavanone G – – – OH – OH R10 OH – OH – –

3-Methyleneflavanone – CH2 – – – – – – – – – – 5,7,4 -Trihydroxy-8-methyl-6-(3-methyl-[2- butenyl])-(2S)-flavanone

– – – OH R3 OH CH3 – – OH – –
Chalcones

Licochalcone A – R11 OH – OCH3 – – – – OH – – Licochalcone C – – OH R3 OCH3 – – – – OH – – 2,4,2 -Trihydroxychalcone OH – OH – – – –

OH – – – – 2,4,2 -Trihydroxy-5 -methylchalcone OH – OH CH3 – – – OH – – – –

T.P.T. Cushnie, A.J. Lamb / International Journal of Antimicrobial Agents 26 (2005) 343–356 347

Table 1 (Continued)

Compound Substituents at carbon position:

234567823456

Flavan-3,4-diols and anthocyanidins

Leucocyanidin – OH OH OH – OH – – OH OH – – Pelargonidin chloride – Cl – OH – OH – – – OH – –

Flavans
6,4 -Dichloroflavan – – – – Cl – – – – Cl – – 7-Hydroxy-3 ,4 -(methylenedioxy)flavan – – – – – OH – – # # – –

R1: Glucuronic acid; R2: glucose; R3: prenyl group; R4: arabinose–galactose; R5: (2 -galloyl)-α-L-arabinopyranoside; R6: rhamnose; R7:
rhamnose–glucose; R8: gallic acid; R9: octanoyl; R10: lavandulyl; R11: 3-methyl-1-butene. –, no substitution; *, pyran ring between positions 2

and 3 ; #, O-CH2-O between positions 3 and 4 . Note: Hinokiflavone and robustaflavone are biflavonoids (also known as biflavonyls) consisting
of two apigenin molecules joined through I-6-O-II-4 and I-6-II-3 linkages, respectively.
wounds. The flavone baicalein is reported to be
The antimicrobial properties of propolis have been largely responsible for this plant’s antimicro- bial
attributed to its high flavonoid content and in effects [28].
particular the presence of the flavonoids galangin
and pinocembrin [12,25–27]. Huang- chin
(Scutellaria baicalensis) is yet another example. This 5. Toxicity of flavonoids
herbal medicine has been used systemically and
topically for thousands of years in China for the It has been suggested that because flavonoids are
treatment of periodontal abscesses and infected oral widely distributed in edible plants and beverages and
have previously been used in traditional medicine, flavus, Cladosporium sphaerospermum, Penicillium
they are likely to have minimal toxicity. However, digitatum and Penicillium italicum [35].
this family of compounds has a diverse range of
activities in mammalian cells [14,20] and in vivo
confirmation of their side effects would be necessary 7. Antiviral activity of flavonoids
for a full evaluation of their practical usefulness in
the field of modern medicine [29]. Given that the A recent area of research that is of particular interest
selectivity of flavonoids for eukaryotic enzymes is the apparent inhibitory activity of some flavonoids
appears to vary from compound to compound against human immunodeficiency virus (HIV). To
[15,20], such a study would need to assess the date, most if not all investigations have involved
toxicity of these phytochemicals on an individual work with the pandemic HIV- 1 strain and its
basis. enzymes. In vitro studies have shown that baicalin
inhibits HIV-1 infection and replication. Inhibition of
HIV-1 entry into cells expressing CD4 and
6. Antifungal activity of flavonoids chemokine co-receptors [36], and antagonism of
HIV-1 reverse transcrip- tase [37] by the flavone
Owing to the widespread ability of flavonoids to O-glycoside have been demonstrated by Li and
inhibit spore germination of plant pathogens, they colleagues. Baicalein [38], robustaflavone and
have been pro- posed for use against fungal hinokiflavone [39] have also been shown to inhibit
pathogens of man [15]. A new prenylated flavanone HIV-1 reverse transcriptase, as have several
recently isolated from the shrub Eysen- hardtia catechins, but catechins inhibit other DNA
texana has been identified as 5,7,4 -trihydroxy-8- polymerases and their interaction with the HIV-1
methyl-6-(3-methyl-[2-butenyl])-(2S)-flavanone and enzyme is therefore thought to be non-specific in
shown to possess activity against the opportunistic nature [40]. In addition, it has been demonstrated that
pathogen Candida albicans [30]. The flavonoid several flavonoids, including demethylated gardenin
7-hydroxy-3 ,4 - (methylenedioxy)flavan, isolated A and 3,2 -dihydroxyflavone, inhibit HIV-1
from Terminalia bellerica fruit rind, has also been proteinase [41]. Robi- netin, myricetin, baicalein,
shown to possess activity against C. albicans[31]. quercetagetin [42] and quercetin 3-O-(2
Two new flavones fromArtemisia giraldi, iden- tified -galloyl)-α-L-arabinopyranoside [43] inhibit HIV-1
as 6,7,4 -trihydroxy-3 ,5 -dimethoxyflavone and 5,5 - integrase, although there are concerns that HIV
dihydroxy-8,2 ,4 -trimethoxyflavone, together with enzyme inhi- bition by quercetagetin and myricetin is
5,7,4 - non-specific [44]. It has also been reported that the
trihydroxy-3 ,5 -dimethoxyflavone have been flavonoids chrysin, acacetin and apigenin prevent
reported to exhibit activity against Aspergillus flavus HIV-1 activation via a novel mech- anism that
[32], a species of fungi that causes invasive disease probably involves inhibition of viral transcrip- tion
in immunosuppressed patients [33]. The activity of [45]. Interestingly, in a study by Hu and colleagues,
propolis against dermatophytes and Candida spp. has chrysin was reported to have the highest therapeutic
been attributed at least partially to its high flavonoid index of 21 natural and 13 synthetic flavonoids
content [34]. Galangin, a flavonol com- monly found against HIV-1 [46].
in propolis samples [24], has been shown to have
inhibitory activity againstAspergillus tamarii,A.
348 T.P.T. Cushnie, A.J. Lamb / International Journal of Antimicrobial Agents 26 (2005) 343–356
[48,49]. It has also been demonstrated that two of the
Several research groups have investigated the flavonoids found in propolis, chrysin and
relationship between flavonoid structure and kaempferol, inhibit viral replication of HSV, human
inhibitory activity against HIV-1 and its enzymes coronavirus and rotavirus [50]. More recently, the
[39,41,42,44,46]. Furthermore, at least two groups flavonol galangin has been reported to have
have proposed mechanisms of action for HIV-1 significant antiviral activity against HSV and
enzyme inhibition [41,42]. coxsackie B virus [51].
Flavonoids also have inhibitory activity against a Although naturally occurring flavonoids with
variety of other viruses. For example, Selway reports antiviral activity have been recognised since the
that quercetin, morin, rutin, dihydroquercetin, 1940s, it is only in the last 25 years that attempts
dihydrofisetin, leucocyani- din, pelargonidin chloride have been made to syn- thetically modify flavonoids
and catechin possess activity against up to seven for improved antiviral activity. One such synthesised
types of virus, including herpes simplex virus (HSV), compound is 6,4 -dichloroflavan. How- ever, despite
respiratory syncytial virus, poliovirus and Sind- bis showing strong in vitro activity, this compound
virus [11,47]. Proposed antiviral mechanisms of proved unsuccessful in clinical trials [11].
action include inhibition of viral polymerase and Synergism has been demonstrated between various
binding of viral nucleic acid or viral capsid proteins com- binations of flavones and flavonols. For
[47]. In addition to the flavonoids mentioned above, example, kaempferol and luteolin show synergy
three proanthocyanidins from Pavetta owariensis against HSV. It has been suggested that this is why
(with structural similarity to proantho- cyanidin A2 propolis is more active than its individual com-
and cinnamtannin B1 and B2) have been shown to ponent compounds [52]. Synergism has also been
have activity against HSV and coxsackie B virus reported between flavonoids and other antiviral
agents. Quercetin, for example, potentiates the glycosides [86,118–120] and chalcones
effects of 5-ethyl-2 -dioxyuridine [11] and acyclovir [79,104,111,121] with antibac- terial activity have
[53] against HSV and pseudorabies infec- tion. also been identified.
Apigenin also enhances the antiviral activity of Some researchers have reported synergy between
acyclovir against these viruses [53]. nat- urally occurring flavonoids and other
antibacterial agents against resistant strains of
bacteria. Examples of these include epicatechin
8. Antibacterial activity of flavonoids gallate [122–125] and sophoraflavanone G [83,84].
At least one group has demonstrated syn- ergy
8.1. Reports of flavonoids possessing antibacterial between flavonoids with antibacterial activity [126].
activity Others have synthetically modified natural flavones
and analysed them for antibacterial activity
The antibacterial activity of flavonoids is being [94,127–131]. For example, Wang and colleagues
increas- ingly documented. Crude extracts from have complexed 5-hydroxy- 7,4 -dimethoxyflavone
plants with a history of use in folk medicine have with a number of transition metals and shown that
been screened in vitro for antibacterial activity by this process increases antibacterial activ- ity [130].
many research groups. Flavonoid- rich plant extracts Another group reported increased antibacterial
from species of Hypericum [54], Capsella [55] and activity of 3-methyleneflavanones when the B ring
Chromolaena [55] have been reported to possess con- tained bromine or chlorine substituents [131].
antibacterial activity. Many other phytochemical Two research groups have described the use of
prepara- tions with high flavonoid content have also flavonoids in vivo. In a study by Vijaya and
been reported to exhibit antibacterial activity Ananthan, oral administration of either 142.9 mg/kg
[22,56–63]. Propolis has been quercetin or 214.3 mg/kg quercetrin pro- tected
analysed on many occasions too, and samples guinea pigs against an induced Shigella infection that
containing high concentrations of flavonoids are killed untreated control animals [132]. More recently,
frequently reported to show antibacterial activity Dasti- dar and co-workers reported that
[12,25–27,50,64]. intraperitoneal injection of either 1.58mg/kg
Many research groups have gone one step further and sophoraisoflavone A or 3.16mg/kg 6,8-
either isolated and identified the structure of diprenylgenistein gave significant protection to mice
flavonoids that possess antibacterial activity, or 8
chal- lenged with ∼9.5×10 colony-forming units
quantified the activity of commercially available (CFUs) of Salmonella typhimurium [110].
flavonoids. Examples of such flavonoids are
apigenin [65–73], galangin [35,74–77], pinocembrin 8.2. Discrepancies between reports of flavonoid
[78,79], ponciretin [80,81], genkwanin [66,82], antibacterial activity
sophoraflavanone G and its derivatives [29,83–85],
naringin and naringenin [29,60,86,87], When reports of the antibacterial activity of
epigallocatechin gallate and its derivatives flavonoids are compared, the results appear widely
[74,88–95], luteolin and luteolin 7- glucoside conflicting (Table 2). For example, it was published
[69,73,96], quercetin, 3-O-methylquercetin and that apigenin had no activity against S. aureus at
various quercetin glycosides [60,65,72,87,97–102] concentrations up to 128μg/mL [72]; a separate study
and kaempferol and its derivatives in the same year reported that the flavone inhibited
[60,65,74,76,87,98,100,103]. Other flavones the growth of 15 strains of MRSA and 5 sensi- tive
[32,60,74,104–107], flavone glyco- sides strains of S. aureus at concentrations between
[86,108,109], isoflavones [110,111], flavanones 3.9μg/mL
[29,30,78,79,104,111–114], isoflavanones [115],
isofla- vans [116], flavonols [74,114,117], flavonol
T.P.T. Cushnie, A.J. Lamb / International Journal of Antimicrobial Agents 26 (2005) 343–356 349

2 elba 0
T
002dna0891neewtebspuorghcraesersuoiravybdenimretedsa,airetcabevitagen-marGdnaevitisop-marGfoseicepssuoremuntsniaganinegipafoytivitcay

rotibihnieh
Tand 15.6μg/mL [73]. From Table 2 it can be seen that such discrepancies could perhaps be attributed on
occasion to dif- ferent assays being used (e.g. [65,70] and [72,73]). Many different assays are employed in flavonoid
research, including the agar dilution technique [29], the paper disk diffusion assay [115], the hole-plate diffusion
method [22], the cylinder diffu- sion method [60], the broth macrodilution technique [71] and the broth microdilution
technique [134]. In particular, assays relying on diffusion of test flavonoids may not give a reliable quantitative
measure of antibacterial activity because a potent antibacterial flavonoid may have a low rate of diffusion [32].
However, it is clear from Table 2 that additional factors are involved in causing these discrepancies because even
groups using the same assay are obtaining conflicting results (e.g. [67,96] and [67,72]). Such inconsistencies may be
due to variations within each assay. For example, different groups using the agar dilution technique have used
different sizes of bacterial inoculum [81,86]. In a report by the National Com- mittee for Clinical Laboratory
Standards (NCCLS), inoculum size was considered the single most important variable in sus- ceptibility testing
[135]. It should be noted that many groups assaying flavonoid antibacterial activity have not quantified the test
bacterial suspension [60,115] and others have not even standardised the size of their unenumerated inocula
[35,56,76,90,97]. From the published work it is clear that, in addition to inoculum size, there are many other variable
factors for each type of assay. These include volume of broth or agar [90,116], type of broth or agar [86,92], size of
wells [56,60], size of paper disks [57,65], strains of a particular bac- terial species used [69,72] and incubation period
[90,116]. Recently, a set of guidelines was published for standard agar dilution, broth macrodilution and broth
microdilution meth- ods [136]. This may help to reduce the number of conflicting reports of flavonoid antibacterial
activity in the future. How- ever, it will remain necessary to consider carefully additional variables such as the
solvent used to dissolve test flavonoids [116,118]. It has previously been shown that precipitation occurs when
selected flavonoids are dissolved in organic solvents and diluted with neutral polar solutions [75]. Precip- itation of
flavonoids in a minimum inhibitory concentration (MIC) assay is likely to cause diminished contact between
bacterial cells and flavonoid molecules and may lead to false negative reports of antibacterial activity. Also, in
improp- erly controlled experiments, flavonoid precipitation could be misinterpreted as bacterial growth and further
false negative results may be recorded as a consequence. The structural alteration of flavonoids such as galangin in
alkaline solvents is another matter for consideration [75]. If flavonoid salts are formed and these have increased or
decreased potency compared with the parent structure, this may lead to false positive/negative reports of antibacterial
activity. Other vari- ables worth noting include whether the test flavonoids are obtained from a commercial or natural
source [35,74] and which companies [74,75]/natural products [71,72] the com- pounds are from.

350 T.P.T. Cushnie, A.J. Lamb / International Journal of Antimicrobial Agents 26 (2005) 343–356
small number of groups which have investigated the
8.3. Structure–activity relationship for antibacterial relationship between flavonoid struc- ture and
activity of flavonoids antibacterial activity (summarised below) have been
able to identify common structural features among
The diverse range of cell functions affected by active compounds. However, it may be that
flavonoids in eukaryotic systems is well documented individual antibacte- rial flavonoids have multiple
[10,20]. Although there have been comparatively few cellular targets, rather than one specific site of action.
studies into the mecha- nisms underlying flavonoid Alternatively, these common structural features may
antibacterial activity, information from published simply be necessary for flavonoids to gain prox-
literature indicates that different compounds within imity to or uptake into the bacterial cell.
this class of phytochemicals may target different Tsuchiya and colleagues sought to establish a
com- ponents and functions of the bacterial cell structure– activity relationship for flavanones by
[137–139]. If this is the case, it is surprising that the isolating a number of differently substituted
compounds and determining their MICs against these compounds. Methoxy groups were reported to
MRSA [29]. Their study indicated that 2 ,4 - or 2 ,6 drastically decrease the antibacterial activ- ity of
-dihydroxylation of the B ring and flavonoids [104]. The importance of hydroxylation at
5,7-dihydroxylation of the A ring in the flavanone the 2 position for antibacterial activity of chalcones
structure was important for anti-MRSA activity. is supported by earlier work from Sato and
Substitution at the 6 or 8 position with a long chain colleagues, who found that 2,4,2 -trihydroxy-5
aliphatic group such as lavandulyl (5-methyl-2- -methylchalcone and 2,4,2 - trihydroxychalcone
isopropenyl-hex-4-enyl) or geranyl inhibited the growth of 15 strains of cariogenic
(trans-3,7-dimethyl-2,6- octadienyl) also enhanced streptococci [140].
activity [29]. Interestingly, a recent report by As mentioned previously, Ward and colleagues syn-
Stapleton and colleagues demonstrated that sub- thesised a number of halogenated derivatives of 3-
stitution with C8 and C10 chains also enhanced the methyleneflavanone [131]. Substitution of the B ring
was found to enhance antibacterial activity, with 3
anti- staphylococcal activity of flavonoids belonging -chloro, 4 - chloro and 4 -bromo analogues each
to the flavan- 3-ol class [94]. being approximately twice as effective as their parent
compound againstS. aureus, and four times more
Osawa et al. assessed the activity of a number of
active against Enterococcus faecalis. Also, the 2 ,4
struc- turally different flavonoids including flavones,
-dichloro derivative exhibited a four- to eight- fold
flavanones, isoflavones and isoflavanones based on
improvement in activity against S. aureus and a two-
the paper disk agar diffusion assay [115]. It was
to four-fold improvement against E. faecalis. By
shown that 5-hydroxyflavanones and
contrast, 3-methylene-6-bromoflavanone was less
5-hydroxyisoflavanones with one, two or three
potent than the par- ent compound and the authors
additional hydroxyl groups at the 7, 2 and 4 positions
suggested that halogenation of the A ring may
inhibited the growth of Streptococcus mutans and
diminish activity [131]. Clearly, however, it would be
Streptococcus sobrinus. These results correlate well
necessary to prepare analogues with substitu- tion at
with those of Tsuchiya and col- leagues [29]. It was
other A-ring positions before this could be said with
also reported by Osawa and colleagues that
any certainty. In chalcones, neither fluorination nor
5-hydroxyflavones and 5-hydroxyisoflavones with
chlo- rination at position 4 of the B ring is reported
addi- tional hydroxyl groups at the 7 and 4 positions
to affect antibacterial potency significantly [104].
did not exhibit this inhibitory activity [115].
Again, however, other structural analogues of this
However, when Sato et al. exam- ined two
class of flavonoids would need to be synthesised and
isoflavones with hydroxyl groups at the 5, 2 and 4
examined before the effect of halogenation upon
positions using an agar dilution assay, intensive
antibacterial activity could be properly assessed.
inhibitory activity was detected against a wide range
of streptococcal species [107]. This may suggest that
hydroxylation at position 2 is important for activity. 8.4. Nature of flavonoid activity: bacteriostatic or
Alternatively, the lack of activity detected by Osawa bactericidal?
et al. may simply be due to the poor diffu- sion of
Several research groups have attempted to determine
flavones and isoflavones (compared with flavanones
whether flavonoid activity is bacteriostatic or
and isoflavanones) through the medium.
bactericidal by conducting time–kill studies. In such
A more recent paper [104] also reports the
experiments, epi- gallocatechin gallate [89], galangin
importance of a hydroxyl group at position 5 of
[75] and 3-O-octanoyl- (+)-catechin [94] have been
flavanones and flavones for activity against MRSA,
shown to cause a reduction of 1000-fold or more in
supporting the earlier findings of
viable counts of MRSA-YK, S. aureus NCTC 6571
Tsuchiya et al. [29]. It further states that chalcones
and EMRSA-16, respectively. This would imme-
are more effective against MRSA than flavanones or
diately appear to suggest that flavonoids are capable
flavones, and that hydroxyl groups at the 2 position
of bac- tericidal activity. However, it has recently
are important for the anti- staphylococcal activity of
been demonstrated that 3-O-octanoyl-(−)-epicatechin questions are raised regarding the interpretation of
induces the formation of pseudomulticellular results from time–kill studies. It may be that
aggregates both in antibiotic-sensitive and flavonoids are not killing bacterial cells but merely
antibiotic-resistant strains of S. aureus [94]. If this inducing the formation of bacterial aggregates and
phe- nomenon is induced by other compounds within thereby reducing the number of CFUs in viable
the flavonoid class (and liposomal studies suggest counts.
that this is the case for epigallocatechin gallate [88]),

T.P.T. Cushnie, A.J. Lamb / International Journal of Antimicrobial Agents 26 (2005) 343–356 351
on DNA and RNA synthesis [138].
8.5. Antibacterial mechanisms of action of various Ohemeng et al. screened 14 flavonoids of varying
flavonoids struc- ture for inhibitory activity against Escherichia
coli DNA gyrase, and for antibacterial activity
8.5.1. Inhibition of nucleic acid synthesis against Staphylococ- cus epidermidis, S. aureus, E.
In a study using radioactive precursors, Mori and coli, S. typhimurium and Stenotrophomonas
col- leagues showed that DNA synthesis was maltophilia [68]. It was found that E. coli DNA
strongly inhibited by flavonoids in Proteus vulgaris, gyrase was inhibited to different extents by seven of
whilst RNA synthesis was most affected in S. aureus the compounds, including quercetin, apigenin and
[138]. Flavonoids exhibiting this activity were 3,6,7,3 ,4 - pentahydroxyflavone. Interestingly, with
robinetin, myricetin and (−)-epigallocatechin. Protein the exception of 7,8-dihydroxyflavone, enzyme
and lipid synthesis were also affected but to a lesser inhibition was limited to those compounds with
extent. The authors suggested that the B ring of the B-ring hydroxylation [68,141]. The authors proposed
flavonoids may play a role in intercalation or that the observed antibacterial activity of the seven
hydrogen bonding with the stacking of nucleic acid flavonoids was due in part to their inhibition of DNA
bases and that this may explain the inhibitory action gyrase. However, since the level of antibacterial
activity and enzyme inhibition did not always further work with mutant strains and purified
correlate, they also suggested that other mechanisms enzymes would be necessary before this could be
verified.
were involved [68].More recently, Plaper and

8.5.2. Inhibition of cytoplasmic membrane function

colleagues reported that quercetin binds to the GyrB
subunit ofE. coliDNA gyrase and inhibits the A research team that had previously found
enzyme’s ATPase activity [142]. Enzyme binding sophorafla- vanone G to have intensive antibacterial
was demonstrated by isolating E. coli DNA gyrase activity against MRSA and streptococci [83–85]
and mea- suring quercetin fluorescence in the recently reported attempts to elucidate the
presence and absence of the gyrase subunits. The mechanism of action of this flavanone [139]. The
flavonoid-binding site was pos- tulated to overlap effect of sophoraflavanone G on membrane flu- idity
with those of ATP and novobiocin, since addition of was studied using liposomal model membranes and
these compounds interfered with quercetin fluo- compared with the less active flavanone naringenin,
rescence. Inhibition of GyrB ATPase activity by which lacks 8-lavandulyl and 2 -hydroxyl groups. At
quercetin was also demonstrated in a coupled concentra- tions corresponding to the MIC values,
ATPase assay. This research is in agreement with the sophoraflavanone G was shown to increase
earlier findings of Ohe- meng et al. [68] and supports fluorescence polarisation of the liposomes
the suggestion that quercetin’s antibacterial activity significantly. These increases indicated an alter- ation
against E. coli may be at least partially attributable to of membrane fluidity in hydrophilic and hydrophobic
inhibition of DNA gyrase. regions, suggesting that sophoraflavanone G reduced
When screening natural products for type II the flu- idity of outer and inner layers of membranes.
Naringenin also exhibited a membrane effect but at
topoisomerase inhibitors, Bernard and co-workers
much higher con- centrations. This correlation
found that the glycosy- lated flavonol rutin was very
between antibacterial activity and membrane
effective [143]. This compound exhibited
interference was suggested to support the theory that
antibacterial activity against a permeable E. coli
sophoraflavanone G demonstrates antibacterial
strain (a strain into which the envA1 allele had been
activity by reducing membrane fluidity of bacterial
incor- porated [144,145]). Using enzyme assays and
cells [139].
a technique known as the SOS chromotest, it was
shown that rutin selec- tively promoted E. coli Another group, Ikigai and colleagues, carried out
topoisomerase IV-dependent DNA cleavage, research on (−)-epigallocatechin gallate, a strongly
inhibited topoisomerase IV-dependent decatena- tion antibacterial cat- echin found in green tea. Catechins
activity and induced the SOS response of the E. coli are a group of flavonoids that appear to have greater
strain. The group suggested that since topoisomerase activity against Gram-positive than Gram-negative
IV is essential for cell survival, the rutin-induced bacteria [88]. In this study, liposomes were again
topoisomerase used as model bacterial membranes, and it was
IV-mediated DNA cleavage leads to an SOS shown that epigallocatechin gallate induced leakage
response and growth inhibition of E. coli cells [143]. of small molecules from the intraliposomal space.
Within our own laboratory, a 4-quinolone-resistant S. Aggregation was also noted in liposomes treated
with the compound. The group therefore concluded
aureus strain was shown to have increased
that catechins primarily act on and damage bacterial
susceptibility to the flavonol galangin compared with
membranes. It was not known how this damage
other 4-quinolone- sensitive and -resistant strains
occurred but two theories were put forward. First,
[146]. Interestingly, this strain possesses a distinct
catechins may perturb the lipid bilayers by directly
amino acid substitution (serine to pro- line) at
penetrating them and disrupting the barrier function.
position 410 of the GrlB subunit. This may suggest
Alterna- tively, catechins may cause membrane
that topoisomerase IV and the relatively homologous
fusion, a process that results in leakage of
gyrase enzyme are involved in the antibacterial
intramembranous materials and aggrega- tion.
mechanism of action of galangin. Clearly, however,
Interestingly, the group also demonstrated that prepared containing nega- tively charged lipids. It
leakage induced by epigallocatechin gallate was was therefore suggested that the low catechin
significantly lower when liposome membranes were susceptibility of Gram-negative bacteria may be at

352 T.P.T. Cushnie, A.J. Lamb / International Journal of Antimicrobial Agents 26 (2005) 343–356
the development of catechins as antibacterial agents
least partially attributable to the presence of and lends support to Ikigai’s argument that catechins
lipopolysaccha- ride acting as a barrier [88]. act on and damage bacterial membranes.
As mentioned previously, Stapleton and colleagues It has also been demonstrated by Sato and colleagues
that the chalcone 2,4,2 -trihydroxy-5
found that substitution with C8 and C10 chains
-methylchalcone induces leakage of 260nm
absorbing substances from S. mutans. This
increased the antibac- terial activity of selected
observation generally indicates leakage of
flavan-3-ols (catechins). The group went on to show
intracellular material such as nucleotide, and the
that cells of an MRSA clinical isolate treated with
authors suggested that 2,4,2 -trihydroxy-5
(−)-epicatechin gallate and
-methylchalcone exerts its antibacterial effect by
3-O-octanoyl-(+)-catechin, respectively, exhibited
changing the permeability of the cellular membrane
moderately and highly increased lev- els of labelling
and damaging membrane function [140].
with the selectively permeable fluorescent stain
In addition, the effect of galangin upon cytoplasmic
propidium iodide. In addition, whenS. aureuscells
were grown in the presence of either (−)-epicatechin integrity in S. aureus has been investigated by
gallate or 3- O-octanoyl-(−)-epicatechin and measuring loss of internal potassium [147]. When
examined by transmission electron microscopy, they high cell densities of S. aureus were incubated for
were shown to form pseudomulti- cellular aggregates 12h in media containing 50μg/mL of the flavonol, a
[94]. This work constitutes a substantial advance in 60-fold decrease in the number of CFUs was noted
and cells lost ca. 20% more potassium than untreated S. aureus and Micrococcus luteus but not against E.
control bacteria. These data strongly suggest that coli, and in preliminary tests licochalcone A
galangin induces cytoplasmic membrane damage and inhibited incorporation of radioactive precursors into
potassium leakage. Whether galangin damages the macromolecules (DNA, RNA and protein). The
mem- brane directly, or indirectly as a result of group hypothesised that the licochalcones may be
autolysis or cell wall damage and osmotic lysis, interfering with energy metabolism in a similar way
remains to be established however [147]. to respiratory-inhibiting antibiotics, since energy is
In an investigation into the antimicrobial action of required for active uptake of various metabolites and
propo- lis, Mirzoeva and colleagues showed that one for biosynthesis of macromolecules [137].
of its con- stituent flavonoids, quercetin, caused an Interestingly, the licochalcones were found to inhibit
increase in perme- ability of the inner bacterial strongly oxygen con- sumption in M. luteus and S.
membrane and a dissipation of the membrane aureus but not in E. coli, which correlated well with
potential [148]. The electrochemical gradient of the observed spectrum of antibacterial activity. The
protons across the membrane is essential for bacteria group further demonstrated that licochalcones A and
to maintain capacity for ATP synthesis, membrane C effectively inhibited NADH-cytochrome c reduc-
transport and motility. Mirzoeva et al. suggested that tase, but not cytochrome c oxidase or NADH-CoQ
the effect of propo- lis on membrane permeability reductase. It was therefore suggested that the
and membrane potential may contribute enormously inhibition site of these retrochalcones was between
to its overall antibacterial activity and may decrease CoQ and cytochrome c in the bacterial respiratory
the resistance of cells to other antibacterial agents. It electron transport chain [137].
was thought that this might explain the synergistic Merck Research Laboratories recently reported that
effect that occurs between propolis and other the flavanone lonchocarpol A inhibits
antibiotics such as tetracycline [148] and ampicillin macromolecular synthesis in Bacillus megaterium.
[149]. The group also demonstrated that the Using radioactive precursors, it was demonstrated
flavonoids quercetin and naringenin significantly that RNA, DNA, cell wall and protein synthesis were
inhibited bacterial motility, providing further all inhibited at concentrations similar to the MIC
evidence that the proton motive force is disrupted. value [150]. This may represent another example of a
Bacte- rial motility and chemotaxis are thought to be flavonoid that interferes with energy metabolism.
important in virulence as they guide bacteria to their
sites of adherence
and invasion. Mirzoeva et al. suggested that the 9. Concluding remarks
antimotil- ity action of propolis components may
have an important role in inhibition of bacterial With regard to natural products, it is generally
pathogenesis and the develop- ment of infection accepted that phytochemicals are less potent
[148]. The cytoplasmic membrane activ- ity detected anti-infectives than agents of microbial origin, i.e.
for quercetin by Mirzoeva and co-workers may antibiotics [48]. However, new classes of
represent one of the additional mechanisms of antimicrobial drug are urgently required and the
antibacterial action that was suspected to be present flavonoids represent a novel set of leads. Future
among the seven DNA gyrase-inhibiting flavonoid optimisation of these compounds through structural
compounds tested by Ohemeng and colleagues [68]. alteration may allow the devel- opment of a
pharmacologically acceptable antimicrobial agent or
8.5.3. Inhibition of energy metabolism group of agents. Existing structure–activity data
Haraguchi and colleagues recently carried out an suggest that it might be possible, for example, to
investi- gation into the antibacterial mode of action prepare a potent antibacterial flavanone by
of two retrochal- cones (licochalcone A and C) from synthesising a compound with halogenation of the B
the roots of Glycyrrhiza inflata[137]. These ring as well as lavandulyl or ger- anyl substitution of
flavonoids demonstrated inhibitory activ- ity against the A ring. Also, it is worth noting that the rapid
progress which is being made toward elucidation

T.P.T. Cushnie, A.J. Lamb / International Journal of Antimicrobial Agents 26 (2005) 343–356 353

of flavonoid biosynthetic pathways [151] may soon The authors are very grateful to Dr Paul Kong and Dr
allow the production of structural analogues of active Satyajit Sarker for critiquing preliminary drafts of
flavonoids through genetic manipulation. Screening the manuscript and for advice on flavonoid
of these analogues might lead to the identification of classification and structure. Thanks are extended to
compounds that are suffi- ciently potent to be useful Dr Peter Taylor for insight- ful comments regarding
as antifungal, antiviral or antibac- terial interpretation of data from time–kill studies with
chemotherapeutics. In addition to the structural alter- flavonoids. Thanks also to Dr Derek Chapman, Miss
ation of weak and moderately active antimicrobial Vivienne Hamilton, Dr Bruce Thomson and Mrs
flavonoids, investigation into the mechanisms of Amina Al-Mossawi for their kind support and
action of these com- pounds is likely to be a encouragement.
productive area of research. Such information may
assist in the optimisation of a lead com- pound’s
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Erratum Errata for “Antimicrobial activity of flavonoids” [Int. J.

Antimicrob. Agents 26 (2005) 343–356]
 ∗
T.P. Tim Cushnie, Andrew J. Lamb
School of Pharmacy, The Robert Gordon University, Schoolhill, Aberdeen AB10 1FR, UK

Errors occurred during typesetting of Table 1 for the above review article. The flavonol morin has hydroxyl groups at
positions 3, 5, 7, 2 and 4 (not 3, 7, 2 , 4 and 5 ), and the flavan-3-ol catechin has hydroxyl groups at positions 3, 5, 7,
3 and 4 (not 3, 4, 7, 3 and 5 ). The structures of these compounds should have been given in Table 1 as shown below.

Table 1 A summary of the structures of antimicrobial flavonoids discussed within the present review article (compiled from The Handbook of
Natural Flavonoids and individual research papers)

Compound Substituents at carbon position

234567823456

Flavonols and their glycosides: Morin – OH – OH – OH – OH – OH – – Flavan-3-ols: Catechin – OH – OH – OH – – OH OH – –

DOI of original article:10.1016/j.ijantimicag.2005.09.002. ∗ Corresponding author. Tel.: +44 1224 262526.

E-mail addresses: [email protected] (T.P.T. Cushnie), [email protected] (A.J. Lamb).

0924-8579/$ – see front matter © 2005 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
doi:10.1016/j.ijantimicag.2005.12.002
International Journal of Antimicrobial Agents 27 (2006) 181