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Antimicrobial activity of flavonoids

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Cushnie TPT, Lamb AJ. Antimicrobial activity of flavonoids. International
Journal of Antimicrobial Agents, 2005. 26(5):343-356.
PMID: 16323269 DOI: 10.1016/j.ijantimicag.2005.09.002

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 International Journal of Antimicrobial Agents 26 (2005) 343–356

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

1. Introduction including ␤-lactams and quinolones [5]. It is not surprising

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

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

1955 [9]. The following review will examine the antimi- neoflavonoid is formed through further isomerisation to the 4
crobial activity of flavonoids, a class of natural products position [13]. Structures of the major classes of flavonoids are
possessing a diverse range of pharmacological properties. given in Fig. 2. The structures of specific compounds within
Compounds with antifungal, antiviral and antibacterial activ- these classes that possess antimicrobial activity and that are
ity will each be discussed in turn, with particular emphasis discussed in the present review are summarised in Table 1.
on those flavonoids with antibacterial activity. Individual flavonoids may be assigned names in three dif-
ferent ways. Trivial names are employed extensively and
sometimes indicate flavonoid class or plant source. For exam-
2. Flavonoids: occurrence, functions, structure and ple, names ending in ‘inidin’ can denote an anthocyanidin,
nomenclature names ending in ‘etin’ generally denote a flavonol, and
compounds tricin and hypolaetin have been extracted from
Flavonoids are ubiquitous in photosynthesising cells and plants belonging to the genera Triticum and Hypolaena.
therefore occur widely in the plant kingdom [10]. They are Flavonoids may also be named in a semi-systematic man-
found in fruit, vegetables, nuts, seeds, stems and flowers as ner based on trivial names such as flavone or chalcone as
well as tea, wine [11], propolis and honey [12], and represent the parent structure, e.g. 3,5,7,3 4 -pentahydroxyflavone or
a common constituent of the human diet [13]. In the US, 3,3 ,4 ,5,7-pentahydroxyflavone. Lastly, flavonoids may be
the daily dietary intake of mixed flavonoids is estimated to given systematic chemical names, e.g. 3,4-dihydro-2-phenyl-
be in the range 500–1000 mg, but this figure can be as high 2H-1-benzopyran for flavan, but this method is cumbersome
as several grams for people supplementing their diets with and rarely used [13]. In the present review, trivial names will
flavonoids or flavonoid-containing herbal preparations [14]. be used wherever possible.
The function of flavonoids in flowers is to provide colours
attractive to plant pollinators [11,15]. In leaves, these com-
pounds are increasingly believed to promote physiologi- 3. Medicinal properties of flavonoids
cal survival of the plant, protecting it from, for example,
fungal pathogens and UV-B radiation [13,15]. In addition, Increasingly, flavonoids are becoming the subject of medi-
flavonoids are involved in photosensitisation, energy transfer, cal research. They have been reported to possess many useful
the actions of plant growth hormones and growth regulators, properties, including anti-inflammatory activity, oestrogenic
control of respiration and photosynthesis, morphogenesis and activity, enzyme inhibition, antimicrobial activity [10,13],
sex determination [11,13]. antiallergic activity, antioxidant activity [11], vascular activ-
The basic structural feature of flavonoid compounds is the ity and cytotoxic antitumour activity [15]. For a group
2-phenyl-benzo[␣]pyrane or flavane nucleus, which consists of compounds of relatively homogeneous structure, the
of two benzene rings (A and B) linked through a heterocyclic flavonoids inhibit a perplexing number and variety of eukary-
pyrane ring (C) (Fig. 1) [16]. Flavonoids can be classified otic enzymes and have a tremendously wide range of activi-
according to biosynthetic origin. Some classes, for exam- ties. In the case of enzyme inhibition, this has been postulated
ple chalcones, flavanones, flavan-3-ols and flavan-3,4-diols, to be due to the interaction of enzymes with different parts of
are both intermediates in biosynthesis as well as end prod- the flavonoid molecule, e.g. carbohydrate, phenyl ring, phe-
ucts that can accumulate in plant tissues. Other classes are nol and benzopyrone ring [10]. Several reviews have been
only known as end products of biosynthesis, for example written on the interaction between flavonoids and mammalian
anthocyanidins, proanthocyanidins, flavones and flavonols. cells, including comprehensive articles by Harborne and
Two additional classes of flavonoid are those in which the Williams [15] and Middleton et al. [20]. An extensive review
2-phenyl side chain of flavanone isomerises to the 3 posi- on the biochemistry and medical significance of flavonoids
tion, giving rise to isoflavones and related isoflavonoids. The has also recently been produced by Havsteen [21].

4. History of flavonoid use in antimicrobial treatment

For centuries, preparations that contain flavonoids as the

principal physiologically active constituents have been used
by physicians and lay healers in attempts to treat human
diseases [10]. For example, the plant Tagetes minuta (contain-
ing quercetagetin-7-arabinosyl-galactoside) has been used
extensively in Argentine folk medicine to treat infectious dis-
ease [22]. The healing properties of propolis (or ‘tzori’ in
Hebrew) are referred to throughout the Old Testament [23],
Fig. 1. The skeleton structure of the flavones (a class of flavonoids), with and this balm was prescribed by Hippocrates (460–377 BC)
rings named and positions numbered [13]. in Ancient Greece for the treatment of sores and ulcers [24].
 T.P.T. Cushnie, A.J. Lamb / International Journal of Antimicrobial Agents 26 (2005) 343–356 345

Fig. 2. The skeleton structures of the main classes of flavonoids: aurones [17,18], isoflavones [10], chalcones [13,19], flavanones [10,13], 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].
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:
2 3 4 5 6 7 8 2 3 4 5 6
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)-␣-l- – OR5 – OH – OH – – OH OH – –
arabinopyranoside
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- – – – OH R3 OH CH3 – – OH – –
butenyl])-(2S)-flavanone
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:

2 3 4 5 6 7 8 2 3 4 5 6
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)-␣-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.

The antimicrobial properties of propolis have been attributed trihydroxy-3 ,5 -dimethoxyflavone have been reported to
to its high flavonoid content and in particular the presence of exhibit activity against Aspergillus flavus [32], a species
the flavonoids galangin and pinocembrin [12,25–27]. Huang- of fungi that causes invasive disease in immunosuppressed
chin (Scutellaria baicalensis) is yet another example. This patients [33]. The activity of propolis against dermatophytes
herbal medicine has been used systemically and topically for and Candida spp. has been attributed at least partially to
thousands of years in China for the treatment of periodontal its high flavonoid content [34]. Galangin, a flavonol com-
abscesses and infected oral wounds. The flavone baicalein is monly found in propolis samples [24], has been shown to
reported to be largely responsible for this plant’s antimicro- have inhibitory activity against Aspergillus tamarii, A. flavus,
bial effects [28]. Cladosporium sphaerospermum, Penicillium digitatum and
Penicillium italicum [35].

5. Toxicity of flavonoids
7. Antiviral activity of flavonoids
It has been suggested that because flavonoids are widely
distributed in edible plants and beverages and have previously A recent area of research that is of particular interest is
been used in traditional medicine, they are likely to have the apparent inhibitory activity of some flavonoids against
minimal toxicity. However, this family of compounds has a human immunodeficiency virus (HIV). To date, most if not
diverse range of activities in mammalian cells [14,20] and in all investigations have involved work with the pandemic HIV-
vivo confirmation of their side effects would be necessary for 1 strain and its enzymes. In vitro studies have shown that
a full evaluation of their practical usefulness in the field of baicalin inhibits HIV-1 infection and replication. Inhibition
modern medicine [29]. Given that the selectivity of flavonoids of HIV-1 entry into cells expressing CD4 and chemokine
for eukaryotic enzymes appears to vary from compound to co-receptors [36], and antagonism of HIV-1 reverse transcrip-
compound [15,20], such a study would need to assess the tase [37] by the flavone O-glycoside have been demonstrated
toxicity of these phytochemicals on an individual basis. by Li and colleagues. Baicalein [38], robustaflavone and
hinokiflavone [39] have also been shown to inhibit HIV-1
reverse transcriptase, as have several catechins, but catechins
6. Antifungal activity of flavonoids inhibit other DNA polymerases and their interaction with
the HIV-1 enzyme is therefore thought to be non-specific
Owing to the widespread ability of flavonoids to inhibit in nature [40]. In addition, it has been demonstrated that
spore germination of plant pathogens, they have been pro- several flavonoids, including demethylated gardenin A and
posed for use against fungal pathogens of man [15]. A new 3,2 -dihydroxyflavone, inhibit HIV-1 proteinase [41]. Robi-
prenylated flavanone recently isolated from the shrub Eysen- netin, myricetin, baicalein, quercetagetin [42] and quercetin
hardtia texana has been identified as 5,7,4 -trihydroxy-8- 3-O-(2 -galloyl)-␣-l-arabinopyranoside [43] inhibit HIV-1
methyl-6-(3-methyl-[2-butenyl])-(2S)-flavanone and shown integrase, although there are concerns that HIV enzyme inhi-
to possess activity against the opportunistic pathogen bition by quercetagetin and myricetin is non-specific [44]. It
Candida albicans [30]. The flavonoid 7-hydroxy-3 ,4 - has also been reported that the flavonoids chrysin, acacetin
(methylenedioxy)flavan, isolated from Terminalia bellerica and apigenin prevent HIV-1 activation via a novel mech-
fruit rind, has also been shown to possess activity against C. anism that probably involves inhibition of viral transcrip-
albicans [31]. Two new flavones from Artemisia giraldi, iden- tion [45]. Interestingly, in a study by Hu and colleagues,
tified as 6,7,4 -trihydroxy-3 ,5 -dimethoxyflavone and 5,5 - chrysin was reported to have the highest therapeutic index
dihydroxy-8,2 ,4 -trimethoxyflavone, together with 5,7,4 - of 21 natural and 13 synthetic flavonoids against HIV-1 [46].
348 T.P.T. Cushnie, A.J. Lamb / International Journal of Antimicrobial Agents 26 (2005) 343–356

Several research groups have investigated the relationship analysed on many occasions too, and samples containing high
between flavonoid structure and inhibitory activity against concentrations of flavonoids are frequently reported to show
HIV-1 and its enzymes [39,41,42,44,46]. Furthermore, at antibacterial activity [12,25–27,50,64].
least two groups have proposed mechanisms of action for Many research groups have gone one step further and
HIV-1 enzyme inhibition [41,42]. either isolated and identified the structure of flavonoids
Flavonoids also have inhibitory activity against a variety that possess antibacterial activity, or quantified the activity
of other viruses. For example, Selway reports that quercetin, of commercially available flavonoids. Examples of such
morin, rutin, dihydroquercetin, dihydrofisetin, leucocyani- flavonoids are apigenin [65–73], galangin [35,74–77],
din, pelargonidin chloride and catechin possess activity pinocembrin [78,79], ponciretin [80,81], genkwanin [66,82],
against up to seven types of virus, including herpes simplex sophoraflavanone G and its derivatives [29,83–85], naringin
virus (HSV), respiratory syncytial virus, poliovirus and Sind- and naringenin [29,60,86,87], epigallocatechin gallate
bis virus [11,47]. Proposed antiviral mechanisms of action and its derivatives [74,88–95], luteolin and luteolin 7-
include inhibition of viral polymerase and binding of viral glucoside [69,73,96], quercetin, 3-O-methylquercetin and
nucleic acid or viral capsid proteins [47]. In addition to the various quercetin glycosides [60,65,72,87,97–102] and
flavonoids mentioned above, three proanthocyanidins from kaempferol and its derivatives [60,65,74,76,87,98,100,103].
Pavetta owariensis (with structural similarity to proantho- Other flavones [32,60,74,104–107], flavone glyco-
cyanidin A2 and cinnamtannin B1 and B2) have been shown sides [86,108,109], isoflavones [110,111], flavanones
to have activity against HSV and coxsackie B virus [48,49]. It [29,30,78,79,104,111–114], isoflavanones [115], isofla-
has also been demonstrated that two of the flavonoids found in vans [116], flavonols [74,114,117], flavonol glycosides
propolis, chrysin and kaempferol, inhibit viral replication of [86,118–120] and chalcones [79,104,111,121] with antibac-
HSV, human coronavirus and rotavirus [50]. More recently, terial activity have also been identified.
the flavonol galangin has been reported to have significant Some researchers have reported synergy between nat-
antiviral activity against HSV and coxsackie B virus [51]. urally occurring flavonoids and other antibacterial agents
Although naturally occurring flavonoids with antiviral against resistant strains of bacteria. Examples of these
activity have been recognised since the 1940s, it is only include epicatechin gallate [122–125] and sophoraflavanone
in the last 25 years that attempts have been made to syn- G [83,84]. At least one group has demonstrated syn-
thetically modify flavonoids for improved antiviral activity. ergy between flavonoids with antibacterial activity [126].
One such synthesised compound is 6,4 -dichloroflavan. How- Others have synthetically modified natural flavones and
ever, despite showing strong in vitro activity, this compound analysed them for antibacterial activity [94,127–131]. For
proved unsuccessful in clinical trials [11]. example, Wang and colleagues have complexed 5-hydroxy-
Synergism has been demonstrated between various com- 7,4 -dimethoxyflavone with a number of transition metals
binations of flavones and flavonols. For example, kaempferol and shown that this process increases antibacterial activ-
and luteolin show synergy against HSV. It has been suggested ity [130]. Another group reported increased antibacterial
that this is why propolis is more active than its individual com- activity of 3-methyleneflavanones when the B ring con-
ponent compounds [52]. Synergism has also been reported tained bromine or chlorine substituents [131]. Two research
between flavonoids and other antiviral agents. Quercetin, for groups have described the use of flavonoids in vivo. In
example, potentiates the effects of 5-ethyl-2 -dioxyuridine a study by Vijaya and Ananthan, oral administration of
[11] and acyclovir [53] against HSV and pseudorabies infec- either 142.9 mg/kg quercetin or 214.3 mg/kg quercetrin pro-
tion. Apigenin also enhances the antiviral activity of acyclovir tected guinea pigs against an induced Shigella infection that
against these viruses [53]. killed untreated control animals [132]. More recently, Dasti-
dar and co-workers reported that intraperitoneal injection of
either 1.58 mg/kg sophoraisoflavone A or 3.16 mg/kg 6,8-
8. Antibacterial activity of flavonoids diprenylgenistein gave significant protection to mice chal-
lenged with ∼9.5 × 108 colony-forming units (CFUs) of
8.1. Reports of flavonoids possessing antibacterial Salmonella typhimurium [110].
activity
8.2. Discrepancies between reports of flavonoid
The antibacterial activity of flavonoids is being increas- antibacterial activity
ingly documented. Crude extracts from plants with a history
of use in folk medicine have been screened in vitro for When reports of the antibacterial activity of flavonoids are
antibacterial activity by many research groups. Flavonoid- compared, the results appear widely conflicting (Table 2).
rich plant extracts from species of Hypericum [54], Capsella For example, it was published that apigenin had no activity
[55] and Chromolaena [55] have been reported to possess against S. aureus at concentrations up to 128 ␮g/mL [72];
antibacterial activity. Many other phytochemical prepara- a separate study in the same year reported that the flavone
tions with high flavonoid content have also been reported inhibited the growth of 15 strains of MRSA and 5 sensi-
to exhibit antibacterial activity [22,56–63]. Propolis has been tive strains of S. aureus at concentrations between 3.9 ␮g/mL
 T.P.T. Cushnie, A.J. Lamb / International Journal of Antimicrobial Agents 26 (2005) 343–356 349

and 15.6 ␮g/mL [73]. From Table 2 it can be seen that such
DD, disk diffusion assay; BMAD, broth macrodilution assay; BMID, broth microdilution assay; NS, assay type not stated in report; AWD, agar well diffusion assay; AD, agar dilution assay; +, antibacterial
Enterobacter Enterobacter Stenotrophomonas

discrepancies could perhaps be attributed on occasion to dif-

maltophilia

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-
cloacae

sion method [60], the broth macrodilution technique [71] and

+

the broth microdilution technique [134]. In particular, assays

aerogenes

relying on diffusion of test flavonoids may not give a reliable

quantitative measure of antibacterial activity because a potent
The inhibitory activity of apigenin against numerous species of Gram-positive and Gram-negative bacteria, as determined by various research groups between 1980 and 2000

antibacterial flavonoid may have a low rate of diffusion [32].

typhimurium

However, it is clear from Table 2 that additional factors are

Salmonella

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

pneumoniae
Klebsiella

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-

mirabilis
Proteus

mittee for Clinical Laboratory Standards (NCCLS), inoculum

+

size was considered the single most important variable in sus-

vulgaris

ceptibility testing [135]. It should be noted that many groups

Proteus

assaying flavonoid antibacterial activity have not quantified

−

−
+
+

the test bacterial suspension [60,115] and others have not

Pseudomonas
aeruginosa

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
Escherichia

or agar [90,116], type of broth or agar [86,92], size of wells

coli

[56,60], size of paper disks [57,65], strains of a particular bac-

−
−

−
+
+

terial species used [69,72] and incubation period [90,116].

Micrococcus

Recently, a set of guidelines was published for standard agar

luteus

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-
Staphylococcus Enterococcus Bacillus
subtilis

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
faecalis

occurs when selected flavonoids are dissolved in organic

+

solvents and diluted with neutral polar solutions [75]. Precip-

epidermidis

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

activity detected; −, no antibacterial activity detected.
Staphylococcus MRSA Staphylococcus

negative reports of antibacterial activity. Also, in improp-

erly controlled experiments, flavonoid precipitation could be
albus

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
aureus

compared with the parent structure, this may lead to false

−
−
−

−
+

positive/negative reports of antibacterial activity. Other vari-

Palacios et al. (DD) [66]

Ohemeng et al. (BMID)

Khanna et al. (DD) [65]

ables worth noting include whether the test flavonoids are

Oksuz et al. (DD) [67]
Miski et al. (DD) [96]

Aljancic et al. (AWD)

Oksuz et al. (BMAD)

Basile et al. (BMAD)

Sato et al. (AD) [73]

obtained from a commercial or natural source [35,74] and

Bashir et al. (NS)

which companies [74,75]/natural products [71,72] the com-

[69,133]
Table 2

[71,72]

pounds are from.

[67]

[68]

[70]
350 T.P.T. Cushnie, A.J. Lamb / International Journal of Antimicrobial Agents 26 (2005) 343–356

8.3. Structure–activity relationship for antibacterial Tsuchiya et al. [29]. It further states that chalcones are more
activity of flavonoids effective against MRSA than flavanones or flavones, and that
hydroxyl groups at the 2 position are important for the anti-
The diverse range of cell functions affected by flavonoids staphylococcal activity of these compounds. Methoxy groups
in eukaryotic systems is well documented [10,20]. Although were reported to drastically decrease the antibacterial activ-
there have been comparatively few studies into the mecha- ity of flavonoids [104]. The importance of hydroxylation
nisms underlying flavonoid antibacterial activity, information at the 2 position for antibacterial activity of chalcones is
from published literature indicates that different compounds supported by earlier work from Sato and colleagues, who
within this class of phytochemicals may target different com- found that 2,4,2 -trihydroxy-5 -methylchalcone and 2,4,2 -
ponents and functions of the bacterial cell [137–139]. If this is trihydroxychalcone inhibited the growth of 15 strains of
the case, it is surprising that the small number of groups which cariogenic streptococci [140].
have investigated the relationship between flavonoid struc- As mentioned previously, Ward and colleagues syn-
ture and antibacterial activity (summarised below) have been thesised a number of halogenated derivatives of 3-
able to identify common structural features among active methyleneflavanone [131]. Substitution of the B ring was
compounds. However, it may be that individual antibacte- found to enhance antibacterial activity, with 3 -chloro, 4 -
rial flavonoids have multiple cellular targets, rather than one chloro and 4 -bromo analogues each being approximately
specific site of action. Alternatively, these common structural twice as effective as their parent compound against S. aureus,
features may simply be necessary for flavonoids to gain prox- and four times more active against Enterococcus faecalis.
imity to or uptake into the bacterial cell. Also, the 2 ,4 -dichloro derivative exhibited a four- to eight-
Tsuchiya and colleagues sought to establish a structure– fold improvement in activity against S. aureus and a two-
activity relationship for flavanones by isolating a number to four-fold improvement against E. faecalis. By contrast,
of differently substituted compounds and determining their 3-methylene-6-bromoflavanone was less potent than the par-
MICs against MRSA [29]. Their study indicated that 2 ,4 - or ent compound and the authors suggested that halogenation
2 ,6 -dihydroxylation of the B ring and 5,7-dihydroxylation of the A ring may diminish activity [131]. Clearly, however,
of the A ring in the flavanone structure was important for it would be necessary to prepare analogues with substitu-
anti-MRSA activity. Substitution at the 6 or 8 position with tion at other A-ring positions before this could be said with
a long chain aliphatic group such as lavandulyl (5-methyl-2- any certainty. In chalcones, neither fluorination nor chlo-
isopropenyl-hex-4-enyl) or geranyl (trans-3,7-dimethyl-2,6- rination at position 4 of the B ring is reported to affect
octadienyl) also enhanced activity [29]. Interestingly, a recent antibacterial potency significantly [104]. Again, however,
report by Stapleton and colleagues demonstrated that sub- other structural analogues of this class of flavonoids would
stitution with C8 and C10 chains also enhanced the anti- need to be synthesised and examined before the effect of
staphylococcal activity of flavonoids belonging to the flavan- halogenation upon antibacterial activity could be properly
3-ol class [94]. assessed.
Osawa et al. assessed the activity of a number of struc-
turally different flavonoids including flavones, flavanones, 8.4. Nature of flavonoid activity: bacteriostatic or
isoflavones and isoflavanones based on the paper disk agar bactericidal?
diffusion assay [115]. It was shown that 5-hydroxyflavanones
and 5-hydroxyisoflavanones with one, two or three additional Several research groups have attempted to determine
hydroxyl groups at the 7, 2 and 4 positions inhibited the whether flavonoid activity is bacteriostatic or bactericidal
growth of Streptococcus mutans and Streptococcus sobrinus. by conducting time–kill studies. In such experiments, epi-
These results correlate well with those of Tsuchiya and col- gallocatechin gallate [89], galangin [75] and 3-O-octanoyl-
leagues [29]. It was also reported by Osawa and colleagues (+)-catechin [94] have been shown to cause a reduction of
that 5-hydroxyflavones and 5-hydroxyisoflavones with addi- 1000-fold or more in viable counts of MRSA-YK, S. aureus
tional hydroxyl groups at the 7 and 4 positions did not exhibit NCTC 6571 and EMRSA-16, respectively. This would imme-
this inhibitory activity [115]. However, when Sato et al. exam- diately appear to suggest that flavonoids are capable of bac-
ined two isoflavones with hydroxyl groups at the 5, 2 and 4 tericidal activity. However, it has recently been demonstrated
positions using an agar dilution assay, intensive inhibitory that 3-O-octanoyl-(−)-epicatechin induces the formation of
activity was detected against a wide range of streptococcal pseudomulticellular aggregates both in antibiotic-sensitive
species [107]. This may suggest that hydroxylation at position and antibiotic-resistant strains of S. aureus [94]. If this phe-
2 is important for activity. Alternatively, the lack of activity nomenon is induced by other compounds within the flavonoid
detected by Osawa et al. may simply be due to the poor diffu- class (and liposomal studies suggest that this is the case for
sion of flavones and isoflavones (compared with flavanones epigallocatechin gallate [88]), questions are raised regarding
and isoflavanones) through the medium. the interpretation of results from time–kill studies. It may
A more recent paper [104] also reports the importance of be that flavonoids are not killing bacterial cells but merely
a hydroxyl group at position 5 of flavanones and flavones inducing the formation of bacterial aggregates and thereby
for activity against MRSA, supporting the earlier findings of reducing the number of CFUs in viable counts.
 T.P.T. Cushnie, A.J. Lamb / International Journal of Antimicrobial Agents 26 (2005) 343–356 351

8.5. Antibacterial mechanisms of action of various IV-mediated DNA cleavage leads to an SOS response and
flavonoids growth inhibition of E. coli cells [143].
Within our own laboratory, a 4-quinolone-resistant S.
8.5.1. Inhibition of nucleic acid synthesis aureus strain was shown to have increased susceptibility
In a study using radioactive precursors, Mori and col- to the flavonol galangin compared with other 4-quinolone-
leagues showed that DNA synthesis was strongly inhibited sensitive and -resistant strains [146]. Interestingly, this strain
by flavonoids in Proteus vulgaris, whilst RNA synthesis was possesses a distinct amino acid substitution (serine to pro-
most affected in S. aureus [138]. Flavonoids exhibiting this line) at position 410 of the GrlB subunit. This may suggest
activity were robinetin, myricetin and (−)-epigallocatechin. that topoisomerase IV and the relatively homologous gyrase
Protein and lipid synthesis were also affected but to a lesser enzyme are involved in the antibacterial mechanism of action
extent. The authors suggested that the B ring of the flavonoids of galangin. Clearly, however, further work with mutant
may play a role in intercalation or hydrogen bonding with the strains and purified enzymes would be necessary before this
stacking of nucleic acid bases and that this may explain the could be verified.
inhibitory action on DNA and RNA synthesis [138].
Ohemeng et al. screened 14 flavonoids of varying struc- 8.5.2. Inhibition of cytoplasmic membrane function
ture for inhibitory activity against Escherichia coli DNA A research team that had previously found sophorafla-
gyrase, and for antibacterial activity against Staphylococ- vanone G to have intensive antibacterial activity against
cus epidermidis, S. aureus, E. coli, S. typhimurium and MRSA and streptococci [83–85] recently reported attempts
Stenotrophomonas maltophilia [68]. It was found that E. coli to elucidate the mechanism of action of this flavanone
DNA gyrase was inhibited to different extents by seven of [139]. The effect of sophoraflavanone G on membrane flu-
the compounds, including quercetin, apigenin and 3,6,7,3 ,4 - idity was studied using liposomal model membranes and
pentahydroxyflavone. Interestingly, with the exception of compared with the less active flavanone naringenin, which
7,8-dihydroxyflavone, enzyme inhibition was limited to lacks 8-lavandulyl and 2 -hydroxyl groups. At concentra-
those compounds with B-ring hydroxylation [68,141]. The tions corresponding to the MIC values, sophoraflavanone
authors proposed that the observed antibacterial activity of G was shown to increase fluorescence polarisation of the
the seven flavonoids was due in part to their inhibition liposomes significantly. These increases indicated an alter-
of DNA gyrase. However, since the level of antibacterial ation of membrane fluidity in hydrophilic and hydrophobic
activity and enzyme inhibition did not always correlate, regions, suggesting that sophoraflavanone G reduced the flu-
they also suggested that other mechanisms were involved idity of outer and inner layers of membranes. Naringenin
[68]. also exhibited a membrane effect but at much higher con-
More recently, Plaper and colleagues reported that centrations. This correlation between antibacterial activity
quercetin binds to the GyrB subunit of E. coli DNA gyrase and and membrane interference was suggested to support the
inhibits the enzyme’s ATPase activity [142]. Enzyme binding theory that sophoraflavanone G demonstrates antibacterial
was demonstrated by isolating E. coli DNA gyrase and mea- activity by reducing membrane fluidity of bacterial cells
suring quercetin fluorescence in the presence and absence [139].
of the gyrase subunits. The flavonoid-binding site was pos- Another group, Ikigai and colleagues, carried out research
tulated to overlap with those of ATP and novobiocin, since on (−)-epigallocatechin gallate, a strongly antibacterial cat-
addition of these compounds interfered with quercetin fluo- echin found in green tea. Catechins are a group of flavonoids
rescence. Inhibition of GyrB ATPase activity by quercetin that appear to have greater activity against Gram-positive
was also demonstrated in a coupled ATPase assay. This than Gram-negative bacteria [88]. In this study, liposomes
research is in agreement with the earlier findings of Ohe- were again used as model bacterial membranes, and it was
meng et al. [68] and supports the suggestion that quercetin’s shown that epigallocatechin gallate induced leakage of small
antibacterial activity against E. coli may be at least partially molecules from the intraliposomal space. Aggregation was
attributable to inhibition of DNA gyrase. also noted in liposomes treated with the compound. The
When screening natural products for type II topoisomerase group therefore concluded that catechins primarily act on
inhibitors, Bernard and co-workers found that the glycosy- and damage bacterial membranes. It was not known how
lated flavonol rutin was very effective [143]. This compound this damage occurred but two theories were put forward.
exhibited antibacterial activity against a permeable E. coli First, catechins may perturb the lipid bilayers by directly
strain (a strain into which the envA1 allele had been incor- penetrating them and disrupting the barrier function. Alterna-
porated [144,145]). Using enzyme assays and a technique tively, catechins may cause membrane fusion, a process that
known as the SOS chromotest, it was shown that rutin selec- results in leakage of intramembranous materials and aggrega-
tively promoted E. coli topoisomerase IV-dependent DNA tion. Interestingly, the group also demonstrated that leakage
cleavage, inhibited topoisomerase IV-dependent decatena- induced by epigallocatechin gallate was significantly lower
tion activity and induced the SOS response of the E. coli when liposome membranes were prepared containing nega-
strain. The group suggested that since topoisomerase IV is tively charged lipids. It was therefore suggested that the low
essential for cell survival, the rutin-induced topoisomerase catechin 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

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

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 International Journal of Antimicrobial Agents 27 (2006) 181

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

2 3 4 5 6 7 8 2 3 4 5 6
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

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