Download Antimicrobial properties of resveratrol: a review

Science against microbial pathogens: communicating current research and technological advances
_______________________________________________________________________________
A. Méndez-Vilas (Ed.)
Antimicrobial properties of resveratrol: a review
L. Paulo1,M. Oleastro2, Eugenia Gallardo1, J.A. Queiroz1 and F. Domingues1
1
CICS-UBI- Centro de Investigação em Ciências da Saúde, Universidade da Beira Interior, Av. Infante D. Henrique,
6201-556 Covilhã, Portugal
2
Unidade Helicobacter/Campylobacter, Laboratório Nacional de Referência de Infecções Gastrentestinais, Departamento
de Doenças Infecciosas, Instituto Nacional Saúde Dr. Ricardo Jorge, I. P., Lisboa, Portugal
Antimicrobial therapy is a powerful tool for the treatment of several diseases, and a keystone of modern medical practice.
However, the increased resistance of microorganisms to the currently used antimicrobials has created the need to evaluate
other agents with potential antimicrobial activity.The phytoalexin resveratrol (3,4’,5-trihydroxistilbene) is commonly
found in food and drinks, such as wines, grapes, vegetables, berries, peanuts and pistachios. This compound is thought to
possess antimicrobial effects, along with antioxidant properties, which are benefic for the prevention of some diseases.
This work reviewed the antimicrobial properties of resveratrol towards pathogenic microorganisms and investigated the
antibacterial properties of resveratrol against different Helicobacter pylori strains. In addition we analysed different
virulence profiles and different susceptibility patterns against the antibiotics that are usually used in anti-H. pylori therapy.
Finally, we verified the ability of resveratrol to inhibit activity of the H. pylori urease, the key enzyme in colonization and
persistence of this pathogen. Nowadays, the use of natural products as antibacterial agents is a promising area of
investigation.
Keywordsresveratrol; antimicrobial activity;Helicobacter pylori;urease
1. Health benefits of resveratrol
Resveratrolis a phytoalexin found in grapes, grape products, wine, peanuts, cranberries,strawberry, and some other
botanical sources. The discovery of resveratrol occurred in 1940, but just in the 90’s were conducted the first studies
showing the beneficial effects of resveratrol on human health. Since then, several papers are published annually
elucidating the benefits of this molecule.
Resveratrol has wide ranging biologicalactivities and consequently many different targets and mechanisms of
action.Resveratrol can prevent or slow the progression of several diseases, including cardiovascular disease [1],
carcinogenic [2, 3] and neurodegenerative [4, 5], prevent many aging processes and increase longevity as
well[6].Resveratrol also has anti-inflammatory [7], antioxidant [8] and antimicrobial properties [9] (see Fig. 1).
Cancer
Chemopreventive
Antioxidant
Anti-inflamatory
Reduces
obesity
Cardio protective
Neuroprotective
Prevents
aging
Fig. 1- Health benefits of resveratrol.
We will now give particular emphasis to the antimicrobial activity of resveratrol, which is one of the objectives of
this review.
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A. Méndez-Vilas (Ed.)
1.1 Antimicrobial properties
Antibacterial therapy is a powerful tool for the treatment ofseveral diseases, and is a keystone of modern
medicinalpractice. However, the increased resistance of microorganismsto the currently used antimicrobials has lead to
theevaluation of other agents with potential antimicrobialactivity[10-12].
During the last century, antimicrobial agents have substantially reduced the threats associated with infectious
diseases. The use of these drugs, combined with improvements in sanitation, housing and nutrition and the existence of
comprehensive immunization programs, has allowed a radical reduction of untreatable infectious diseases, often fatal,
contributing to increased life expectancy. However, the adaptation of microorganisms own defences against the
antibiotics used has made the development, proliferation and persistence of antimicrobial resistance, a currently major
public health problem, making urgent the discovery of new drugs endowed with antimicrobial activity [13, 14].
It is important to note that, besides the importance of finding new antibiotics to be used as drugs, there is also a huge
research in developing new preservatives in food industry. Thus, although most synthetic preservatives are effective,
there is a greater concern of consumers about their health, which means that there is a growing interest in new
antimicrobial compounds obtained from natural sources [15]. In recent years, an increasing interest has been developed
in biologically active compounds including antioxidants from plants and other natural sources [16].
Thus, resveratrol, in addition to the biological activities described above, has been the subject of study for its ability to
inhibit the growth of some pathogenic microorganisms such as Gram-positive and Gram-negative bacteria and fungi
[17-20]. Table 1 presents a review of the published studies about the antimicrobial activity of this compound.
Table 1Review of literature on the antimicrobial activity of resveratrol.
Sample
Resveratrol
Resveratrol
Resveratrol
Resveratrol
extracted
from wine
Resveratrol
isolated
from seeds
of melinjo
(Gnetumgne
monL.)
1226
Strain
Cronobacter sakazakii Fec39
Cronobacter sakazakii MSDH
Xylella fastidiosa Temecula
Xylella fastidiosa Conn Creek
Xylella fastidiosa Dixon Almond
Xylella fastidiosa Tulare
Bacillus cereus ATCC 11771
Staphylococcus aureus ATCC 25923
Staphylococcus aureus MSSA
Staphylococcus aureus MRSA
Staphylococcus aureus MRSA
Enterococcus faecalis ATCC 29212
Escherichia coli ATCC 25922
Escherichia coli clinical strain
Klebsiella pneumoniae ATCC 13883
Klebsiella pneumoniae clinical strain
Salmonella typhimurium ATCC 13311
Pseudomonas aeruginosa ATCC 27853
Pseudomonas aeruginosaclinical strain
Salmonella enterica ATCC 13076
Escherichia coli ATCC 25922
Bacillus subtilis Marburg 168
Luconostoc mesenteroides 9a4
Lactobacillus plantarum NRIC1067
Escherichia coli IFO3301
Saccharomyces cerevisiae IFO2347
Penicillium expansum IFO6096
Clostridium perfringens NCT8238
Bifidobacterium bifidum NRBC100015
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Methods
Reference
Broth
Dilution
[21]
Agar Dilution
[22]
Disk
Diffusion,
Microdilution
and Time-kill
Curves
[23]
Time-kill
Curves
[24, 25]
Agar Dilution
[26]
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A. Méndez-Vilas (Ed.)
Sample
Resveratrol
isolated
from grapes
Strain
Helicobacter pyloriclinical strain G21, cagA negative
Methods
Reference
Helicobacter pyloriclinical strain 10K, cagA positive
(cagA+)
Microdilution
[27]
Disk
Diffusion and
Microdilution
[28]
Agar Dilution
[29]
Agar Dilution
and
Microdilution
[15]
Broth
Dilution
[9]
Candida albicans ATCC 90028
Cryptococcus neoformans ATCC 90112
Staphylococcus aureus ATCC 29213
Streptococcus pneumoniae ATCC 6303
Enterococcus faecalis ATCC 29212
Resveratrol
Micrococcus luteus Presque Isle 456
Stenotrophomonas maltophilia ATCC 13637
Escherichia coli ATCC 25922
Enterobacter cloacae ATCC 13047
Neisseria gonorrhoeae ATCC 49226
Resveratrol
Resveratrol
Resveratrol
Candida albicans ATCC 90028
Candida albicans ATCC 76615
Candida albicans SC 5314
Candida dubliniensis CBS 8500
Candida tropicalis ATCC 750
Candida tropicalis ATCC 90874
Candida parapsilosis Y 05.01
Candida glabrata Y 33.90
Candida krusei ATCC 90878
Bacillus cereus
Listeria monocytogenes
Staphylococcus aureus
Escherichia coli ATCC 25922
Salmonella anatum
Propionibacterium acnes ATCC 25746
Propionibacterium acnes ATCC 29399
Propionibacterium acnes ATCC 33179
Resveratrol
extracted
from grapes
Candida albicans TIMM 1768
Time-kill
Curves
[30]
Resveratrol
Proteus mirabilis P19, WT
Proteus mirabilis P1100
Proteus mirabilis Pc
Agar Dilution
[31]
Protykin®
(containing
50% of
resveratrol)
Helicobacter pylori ATCC 49503
Broth
Dilution
[32]
Resveratrol
Aspergillus flavus KCTC 1375
Saccharomyces cerevisiae KCTC 7296
Trichosporon beigelii KCTC 7707
Candida albicans TIMM 1768
Microdilution
and Time-kill
Curves
[33]
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Sample
Strain
Methods
Reference
Resveratrol
Helicobacter pylori OMU 89–362
Time-kill
Curves
[34]
Protykin®
(containing
50% of
resveratrol)
and
resveratrol
Helicobacter pylori ATCC 49503
Broth
Dilution
[35]
Resveratrol
Penicillium expansum DBM 4061
Aspergillus niger DMF 0801
Botrytis cinerea DBM 4111
Saccharomyces cerevisiae DBM 181
Broth
Dilution
[8]
Agar Dilution
[36]
Microdilution
[37]
Microdilution
[20]
Microdilution
[19]
Two
extracts of
red wine
and
resveratrol
Resveratrol
Resveratrol
Resveratrol
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Helicobacter pyloricagA+ M23-3
Helicobacter pyloricagA+ GTD7-13
Helicobacter pyloricagA+ G1-1
Helicobacter pyloricagA+ SS1
Helicobacter pylori ATCC43504
Stenotrophomonas maltophilia
Micrococcus luteus
Staphylococcus aureus
Escherichia coli
Enterobacter cloacae
Enterococcus faecalis
Streptococcus pneumoniae
Neisseria gonorrhoeae
Candida albicans
Cryptococcus neoformans
Staphylococcus aureus 8325-4 WT
Staphylococcus aureus 1758
Escherichia coli K-12 WT
Escherichia coli KLE701
Pseudomonas aeruginosa PA767 WT
Pseudomonas aeruginosa K1119
Salmonella enterica ST329 WT
Pseudomonas syringae pv. maculicolaES4326 WT
Xanthomonas campestris XCC528 WT
Agrobacterium tumefaciens GV3101 WT
Erwinia rhapontici Er1 WT
Erwinia carotovora ATCC 358 WT
Sinorhizobium meliloti Rm1021 WT
Bacillus megaterium 11561 WT
Staphylococcus aureus ATCC 29213
Enterococcus faecalis ATCC 29212
Pseudomonas aeruginosa ATCC 27853
Trichophyton mentagrophytes ATCC 18748
Trichophyton tonsuransATCC 28942
Trichophytonrubrum ATCC 18762
Epidermophyton floccosum ATCC 52066
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A. Méndez-Vilas (Ed.)
Sample
Sixteen
Chilean
wines, two
selected
extracts and
resveratrol
Resveratrol
Red wine
extract and
resveratrol
Strain
Microsporum gypseum ATCC 14683
Methods
Reference
Disk
Diffusion
[38]
Agar Dilution
[18]
Agar Dilution
[17]
5 clinical isolates of Helicobacter pylori
Helicobacter pylori ATCC 43504
Neisseria gonorrhoeae
Neisseria meningitidis ATCC 13090
Escherichia coli
Staphylococcus aureus
Streptococcus pyogenes
Pseudomonas aeruginosa
Candida albicans
15 clinical isolates of Helicobacter pylori
Helicobacter pylori ATCC 43504
MSSA Methicillin-SensitiveStaphylococcus aureus; MRSA Methicillin-ResistantStaphylococcus aureus;
ATCC American Type Culture Collection; WT Wild Type
According to these results, resveratrol has potential due to its antimicrobial properties and may in the future be used
in the treatment and prevention of infections caused by certain pathogens.
Oneof the aimsof this work was to evaluate the antibacterial properties of resveratrol towards different Helicobacter
pylori strains. In addition, we verified the ability of resveratrol to inhibit activity of the H. pylori urease, the key enzyme
in colonization and persistence of this pathogen.
2. Helicobacter pylori
2.1 Brief History
In 1982 two Australian researchers, Barry Marshall and Robin Warren, discovered that all the patientswith duodenal
ulcers and 80% of the patients with gastric ulcers had a common characteristic: theyhad a spiral-shaped non-identified
bacteria present in their gastrointestinal tract. Based on theseobservations they suggested that the bacteria was the
principal cause of gastritis and peptic ulcer[39]. The discovery of the bacterium H. pylori and its role in gastritis and
peptic ulcer disease resulted in a Nobel Prize in Medicine for Marshall and Warren in 2005. During the following 10
years, research from all over the world confirmed the presence of H.pylori in patients with peptic ulcer disease.
Moreover, in 1994, the International Agency for Research on Cancer (IARC), a World Health Organization agency
included H. pylori as a group 1 carcinogen in humans.
Since those early days, many advances in the understanding of H. pyloriand particularcharacteristics were achieved.
A great deal of the bacterium’s biochemical pathways hasbeen identified, the prevalence in the human population in
several countries all around theworld described, and its role in certain human diseases such as gastritis and stomach
ulcerclarified. Research has also allowed for the development of reliable diagnostic methodsfor H. pylori infection and
suitable treatment procedures.
The peculiarity of H. pylori has also turned the bacteria into one of the hot-topics for scientists. Between 1990 and
2010, an average of more than 2000 papers was published annuallyin international peer-reviewed journals(Fig. 2). It
was also one of the first bacteria to havethe genome sequenced for two different strains, J99 [40] and 26695 [41].
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Number of Publications
35000
30000
25000
20000
15000
10000
5000
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
0
Yea
ar
Fig. 2- Plot of
o the number of publicationns per year in international peer-reviewed
p
j
journals,
as obbtained using th
he ISI Web off
Knowledge seearch. The searcch was performeed with the worrds “Helicobactter AND pylorii”.
2.2 Predominancce worldwide
H. pylori occcurs worldwiide and affects on averagee approximateely 50% of thhe world poppulation [42], although thee
incidence haas been decreaasing in recennt years [43].. Distribution appears to have
h
a higher incidence in undevelopedd
countries andd a low inciddence in deveeloped countrries (Fig. 3). In undeveloped countries reaches abou
ut 80% of thee
population annd the infectioon rate has rem
mained constaant; in develop
ped countries reaches abouut 40%, observ
ving a declinee
in prevalencee due to improovements in thhe hygiene andd sanitation [4
43].
Fig. 33 Worldwide prevalenceofHe
p
elicobacterpylorri[44].
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2.3Virulence facctors
Helicobacterr pylori is a Gram-negativve spiral-shapped, fastidiouss, microaerophilic bacillus which rapidlly hydrolysess
urea as part of its adaptedd survival metthods [45, 46]]. It has been implicated ass the etiologicc agent of chrronic gastritis,,
peptic ulcer, gastric adenoocarcinoma annd related gasttroduodenal disorders
d
[47].. Several poteential virulence factors mayy
be responsibble for the pathogenicitty of H. pyylori, such as
a the cytottoxin-associatted gene A (cagA), thee
vacuolatingccytotoxin A (vvacA) and urrease [45]. Thhe cagA and vacA genes are the two major H. pyllori virulencee
markers. Thee cagA gene is a strain-speccific gene, belonging to thee cag pathogeenicity island, which has beeen associatedd
with severe gastric
g
disease [48, 49]. Thhe vacA gene encodes for a vacuolatingg toxin and is characterized
d by a mosaicc
structure for which differeent alleles havve been identiified in the sig
gnal (s), midddle and interm
mediate region
ns of the genee
s type has beeen associatedd with in vitrrocytotoxin acctivity [52]. T
The bacteria produces
p
highh
[50, 51]. Onnly the vacA s1
levels of the enzyme ureasse which convverts urea intoo ammonia, prroducing a loccal alkaline ennvironment that enables thee
o the gastricc
organism to survive on thhe acidic envvironment of the stomach as well as aidds its initial ccolonization of
4
mucosa [53, 54] (see Fig. 4).
Fig. 4-Helicobbacter pyloria Electron
E
microggraph and b schhematic represeentation showing shape, polar fflagella, urease, H+-gated ureaa
channel and thhe production of ammonia [45]].
2.44 Anti-Helicobbacter pylori activity of ressveratrol
In recent yeaars, and due too a worrying rise in the preevalence of an
ntibiotic resisttant strains, w
we assisted to an increasingg
interest in biiologically active compounnds including antioxidants from plants and
a other natuural sources. Indeed, somee
epidemiologiical studies have
h
shown a correlation between sero
opositivity too H. pylori aand environm
mental factors,,
including dieet[55,56]. Thee phytoalexin resveratrol (3,4’,5-trihydroxistilbene) haas been attribuuted to numero
ous beneficiall
biological efffects[2, 57, 58], includinng potent antiimicrobial activity[9, 15, 17, 19, 23, 331, 36, 38] as
a previouslyy
mentioned.
d
strainns of H. pylorri was examin
ned (Table 2))
In this woork, the antibaacterial activiity of resverattrol against different
[59].
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Table 2.Helicobacter pylori strains characterization regarding virulence factors, antibiotic and resveratrol susceptibility.
Virulence
factor
Strain Numbera
cagA
vacAc
Antibiotic
susceptibility
Metronidazole
MIC
1692/05
94/99
957/03
18/99
67/99
1152/04
1776/05
32/00
1025/03
553A/02
184/99
8/00
5/00
690/99
565/99
+
+
+
+
+
+
+
+
+
-
+
+
+
+
+
+
+
+
-
24
0.5
24
257
257
0.094
0.19
0.5
0.19
0.047
0.19
0.19
0.064
0.38
0.094
Clarithromycin
MIC
R
S
R
R
R
S
S
S
S
S
S
S
S
S
S
>256
257
0.016
0.032
0.032
<0.016
0.016
0.5
< 0.016
0.023
0.016
0.016
0.015
0.032
257
R
R
S
S
S
S
S
S
S
S
S
S
S
S
R
Ciprofloxacin
MIC or
inhibition
diameterb
46b
0.094
40 b
0.125
0.016
55 b
42 b
0.125
50 b
51 b
0.064
0.023
0.032
0.032
0.094
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
Resveratrol
susceptibility
Disk
Agar
Diffusion Dilution
Inhibition
diameter
MIC
21.7
16.3
17.3
23.3
20.7
19.7
18.5
17.3
26.7
19.8
20.5
22.8
27.8
21.3
19.7
50
50
50
100
100
50
50
50
25
50
50
25
25
50
50
MIC - Minimum inhibitory concentration (µg/mL). - negative; + positive; S- sensitive; R- resistant; a H. pylori strains are indicated
by their collection number.b The inhibition diameter is measured in mm; disk diffusion method. cThe vacA status was determined
according to the presence of the s1 toxigenic allele (vacA positive) or s2 nontoxigenicallele (vacA negative).
In addition we analyzed different virulence profiles and different susceptibility patterns against the antibiotics that
are usually used in anti-H. pylori therapy. The diameter of inhibition zone and the minimum inhibitory concentration
(MIC) were evaluated (Table 2). From the results of the disk diffusion assay we observed that resveratrol prevented the
growth of all tested strains, with the inhibition diameters of growth ranging from 16.3 to 27.8 mm (Table 2), indicating
a variable susceptibility of the strains to resveratrol. The observed differences may be explained by the fact that the
strains are very heterogeneous, presenting different virulence profiles and diverse antibiotics susceptibility patterns[27,
36].Using theagar dilution method, the MIC was determined for all strains. The MIC ranged between 25 and 100
µg/mL, with the majority of the strains presenting a similar susceptibility pattern (MIC=50 µg/mL) (Table 2).The three
H. pylori strains that were inhibited with the lowest resveratrol concentration were susceptible to all the antibiotics
tested, two of them (strains 8/00 and 5/00) were negative for both cagA and vacAgenes and thethird strain (1025/03)
was positive for cagAand negative for vacA[59]. In contrast, resveratrol showed less activity against strains 67/99 and
18/99 (MIC= 100 µg/mL), which were positive for both virulence factors and resistant to metronidazole (Table 2)
[59].These results were consistent with previous studies demonstrating that resveratrol has different antibacterial
activity against various H. pylori strains [17, 27, 32, 34-36, 38, 60-62]. According to the literature, resveratrol exhibits
the most potent inhibitory activity on H. pylori infection under neutral conditions [34].
2.4.1 Urease
H. pylori is a unique bacteria that can survive in the acidic environment of animal stomach since it has the ability to
neutralize gastric acids with ammonia produced by urease. In this study, the urease inhibitory activity of resveratrol,
acetohydroxamic acid (AHA) (as positive control) and two red wine samples with different amounts of resveratrol were
tested. The studied concentrations of resveratrol and AHA ranged from 6.25 to 400 µg/mL (Fig. 5).
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A. Méndez-Vilas (Ed.)
Fig. 5-Inhibitory effect of various concentrations (6.25-400 µg/mL) of resveratrol and acetohydroxamic acid on the urease
activity.Resveratrol, filled symbols, and AHA, open symbols, in three Helicobacterpylori strains: 26695, squares, 1692/05 circles
and 553A/02 triangles. Data corresponds to the average of three experiments.
Our results demonstrated that the addition of resveratrol decreased urease activity in the three H. pylori strains tested,
and this inhibitory effect was proportional to the concentration of resveratrol. For the three strains tested, a decrease of
90% in the ureaseactivity was observed for a concentration of 400 µg/mLof resveratrol. In identical concentrations,
AHA exhibited lower urease inhibitory activity, 72, 49 and 73%, for strains 26695, 1692/05 and 553A/02, respectively.
According to these results, resveratrol exhibited higher in vitro urease inhibitory activity than AHA. The analysis of the
slopes and shapes of the semilog curves of resveratrolsuggests that different strains of H. pylori react differently to the
presence of resveratrol.
On a global scale the burden of disease due to H. pylori is enormous; elimination of these bacteria would have a
major impact on present and future world health. Diagnosis and therapy constitute the only treatment at present,
however current treatments are not an effective strategy.Thus, the availability of new anti-H.pylori compounds opens up
new expectations to fight this infectious disease.
Acknowledgements The support by FCT, the Portuguese Foundation for Science and Technology (SFRH/BD/28168/2006) is
gratefully acknowledged.
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