Antimicrobial properties of resveratrol: a review

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

2Unidade 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).

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.

Anti-inflamatory

Cancer Chemopreventive Antioxidant

Reduces obesity

Neuroprotective

Cardio protective

Prevents aging

1225©FORMATEX 2011

Science against microbial pathogens: communicating current research and technological advances 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 Strain Methods Reference

Resveratrol Cronobacter sakazakii Fec39 Broth

Dilution [21]

Cronobacter sakazakii MSDH

Resveratrol

Xylella fastidiosa Temecula

Agar Dilution [22] Xylella fastidiosa Conn Creek

Xylella fastidiosa Dixon Almond

Xylella fastidiosa Tulare

Resveratrol

Bacillus cereus ATCC 11771

Disk Diffusion,

Microdilution and Time-kill

Curves

[23]

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

Resveratrol extracted from wine

Salmonella enterica ATCC 13076 Time-kill Curves

[24, 25] Escherichia coli ATCC 25922

Resveratrol isolated

from seeds of melinjo

(GnetumgnemonL.)

Bacillus subtilis Marburg 168

Agar Dilution [26]

Luconostoc mesenteroides 9a4

Lactobacillus plantarum NRIC1067

Escherichia coli IFO3301

Saccharomyces cerevisiae IFO2347

Penicillium expansum IFO6096

Clostridium perfringens NCT8238

Bifidobacterium bifidum NRBC100015

1226 ©FORMATEX 2011

Science against microbial pathogens: communicating current research and technological advances A. Méndez-Vilas (Ed.)______________________________________________________________________________


Resveratrol isolated

from grapes

Helicobacter pyloriclinical strain G21, cagA negative

Microdilution [27] Helicobacter pyloriclinical strain 10K, cagA positive (cagA+)

Resveratrol

Candida albicans ATCC 90028

Disk Diffusion and Microdilution

[28]

Cryptococcus neoformans ATCC 90112


Streptococcus pneumoniae ATCC 6303


Micrococcus luteus Presque Isle 456

Stenotrophomonas maltophilia ATCC 13637

Escherichia coli ATCC 25922

Enterobacter cloacae ATCC 13047

Neisseria gonorrhoeae ATCC 49226

Resveratrol


Agar Dilution [29]


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

Resveratrol

Bacillus cereus

Agar Dilution and

Microdilution [15]

Listeria monocytogenes

Staphylococcus aureus

Escherichia coli ATCC 25922 Salmonella anatum

Resveratrol

Propionibacterium acnes ATCC 25746 Broth

Dilution [9] 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

Agar Dilution [31] Proteus mirabilis P1100

Proteus mirabilis Pc

Protykin® (containing

50% of resveratrol)

Helicobacter pylori ATCC 49503 Broth

Dilution [32]

Resveratrol

Aspergillus flavus KCTC 1375 Microdilution and Time-kill

Curves [33]

Saccharomyces cerevisiae KCTC 7296

Trichosporon beigelii KCTC 7707

Candida albicans TIMM 1768

1227©FORMATEX 2011



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

Broth Dilution

[8] Aspergillus niger DMF 0801

Botrytis cinerea DBM 4111

Saccharomyces cerevisiae DBM 181

Two extracts of red wine

and resveratrol

Helicobacter pyloricagA+ M23-3

Agar Dilution [36]

Helicobacter pyloricagA+ GTD7-13

Helicobacter pyloricagA+ G1-1

Helicobacter pyloricagA+ SS1

Helicobacter pylori ATCC43504

Resveratrol

Stenotrophomonas maltophilia

Microdilution [37]

Micrococcus luteus


Escherichia coli

Enterobacter cloacae

Enterococcus faecalis

Streptococcus pneumoniae

Neisseria gonorrhoeae

Candida albicans

Cryptococcus neoformans

Resveratrol

Staphylococcus aureus 8325-4 WT

Microdilution [20]

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

Resveratrol


Microdilution [19]


Pseudomonas aeruginosa ATCC 27853

Trichophyton mentagrophytes ATCC 18748

Trichophyton tonsuransATCC 28942

Trichophytonrubrum ATCC 18762

Epidermophyton floccosum ATCC 52066




Microsporum gypseum ATCC 14683

Sixteen Chilean

wines, two selected

extracts and resveratrol

5 clinical isolates of Helicobacter pylori

Disk Diffusion

[38]

Helicobacter pylori ATCC 43504

Resveratrol

Neisseria gonorrhoeae

Agar Dilution [18]

Neisseria meningitidis ATCC 13090

Escherichia coli


Streptococcus pyogenes

Pseudomonas aeruginosa

Candida albicans Red wine

extract and resveratrol

15 clinical isolates of Helicobacter pylori Agar Dilution [17]

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].

1229©FORMATEX 2011


Fig. 2- Plot oKnowledge se

2.2

H. pylori ocincidence hacountries andpopulation anin prevalence

of the number earch. The searc

Predominanc

ccurs worldwias been decread a low incidnd the infectioe due to impro

50

100

150

200

250

300

350

Nu

mb

er o

f P

ub

lica

tion

s

of publicationch was performe

ce worldwide

ide and affecasing in recendence in deveon rate has removements in th

Fig. 3

0

00

00

00

00

00

00

00

1990

1991

1992

ns per year in ed with the wor

ts on averagent years [43].eloped countrmained constahe hygiene and

3- Worldwide p

1992

1993

1994

1995

1996

international prds “Helicobact

e approximate. Distributionries (Fig. 3). ant; in developd sanitation [4

prevalenceofHe

1996

1997

1998

1999

2000

Yea

peer-reviewed jter AND pylori

ely 50% of thappears to h

In undevelopped countries 43].

elicobacterpylor

2000

2001

2002

2003

2004

ar

journals, as obi”.

he world pophave a higher ed countries reaches abou

ri[44].

2004

2005

2006

2007

2008

btained using th

pulation [42], incidence in

reaches abouut 40%, observ

2008

2009

2010

he ISI Web of

although theundeveloped

ut 80% of theving a decline

f

e d e e



2.3

Helicobacterurea as part peptic ulcer, be responsibvacuolatingcmarkers. Thewith severe gstructure for [50, 51]. Onlevels of the organism to mucosa [53,

Fig. 4-Helicobchannel and th

2.4

In recent yeainterest in biepidemiologiincluding diebiological efmentioned. In this wo[59].

Virulence fac

r pylori is a of its adaptedgastric adenoble for the

cytotoxin A (ve cagA gene igastric diseaswhich differe

nly the vacA senzyme ureassurvive on th54] (see Fig. 4

bacter pyloria Ehe production o

4 Anti-Helicob

ars, and due toiologically acical studies het[55,56]. Theffects[2, 57,

ork, the antiba

ctors

Gram-negativd survival metocarcinoma an

pathogenicitvacA) and urs a strain-spece [48, 49]. Thent alleles havs1 type has bese which convhe acidic env4).

Electron microgf ammonia [45]

bacter pylori

o a worrying tive compoun

have shown ae phytoalexin 58], includin

acterial activi

ve spiral-shapthods [45, 46]nd related gastty of H. pyrease [45]. Thcific gene, behe vacA gene ve been identieen associatedverts urea intovironment of

graph and b sch].

activity of res

rise in the prends including a correlation resveratrol (3

ng potent anti

ity of resverat

ped, fastidious]. It has been troduodenal dylori, such ahe cagA and longing to theencodes for

ified in the sigd with in vitr

o ammonia, prthe stomach

hematic represe

sveratrol

evalence of anantioxidants between sero

,4’,5-trihydroimicrobial ac

trol against d

s, microaeropimplicated as

disorders [47].as the cytotvacA genes

e cag pathogea vacuolatinggnal (s), middrocytotoxin acroducing a locas well as aid

entation showin

ntibiotic resistfrom plants aopositivity toxistilbene) hativity[9, 15,

different strain

hilic bacillus s the etiologic. Several potetoxin-associatare the two

enicity island, g toxin and is dle and intermctivity [52]. Tcal alkaline ends its initial c

g shape, polar f

tant strains, wand other natuo H. pylori aas been attribu17, 19, 23, 3

ns of H. pylor

which rapidlc agent of chrential virulencted gene A major H. pylwhich has becharacterized

mediate regionThe bacteria pnvironment thcolonization o

flagella, urease

we assisted to ural sources. and environmuted to numero31, 36, 38] a

ri was examin

ly hydrolysesronic gastritis,e factors may

(cagA), thelori virulenceeen associatedd by a mosaicns of the geneproduces highat enables theof the gastric

, H+-gated urea

an increasingIndeed, some

mental factors,ous beneficialas previously

ned (Table 2)

s ,

y e e d c e h e c

a

g e , l y

)

1231©FORMATEX 2011


Table 2.Helicobacter pylori strains characterization regarding virulence factors, antibiotic and resveratrol susceptibility.

Virulence

factor

Antibiotic susceptibility

Resveratrol susceptibility

Strain Numbera cagA vacAc Metronidazole Clarithromycin Ciprofloxacin Disk

Diffusion Agar

Dilution

MIC MIC MIC or

inhibition diameterb

Inhibition diameter

MIC

1692/05 + + 24 R >256 R 46b S 21.7 50 94/99 + + 0.5 S 257 R 0.094 S 16.3 50 957/03 + + 24 R 0.016 S 40 b S 17.3 50 18/99 + + 257 R 0.032 S 0.125 S 23.3 100 67/99 + + 257 R 0.032 S 0.016 S 20.7 100

1152/04 + + 0.094 S <0.016 S 55 b S 19.7 50 1776/05 + + 0.19 S 0.016 S 42 b S 18.5 50 32/00 + + 0.5 S 0.5 S 0.125 S 17.3 50

1025/03 + - 0.19 S < 0.016 S 50 b S 26.7 25 553A/02 - - 0.047 S 0.023 S 51 b S 19.8 50 184/99 - - 0.19 S 0.016 S 0.064 S 20.5 50 8/00 - - 0.19 S 0.016 S 0.023 S 22.8 25 5/00 - - 0.064 S 0.015 S 0.032 S 27.8 25

690/99 - - 0.38 S 0.032 S 0.032 S 21.3 50 565/99 - - 0.094 S 257 R 0.094 S 19.7 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).



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.

References

[1] Bradamante S, Barenghi L, Villa A. Cardiovascular protective effects of resveratrol. Cardiovascular Drug Reviews.2004; 22: 169- 188.

[2] Jang M, Cai L, Udeani GO, Slowing KV, Thomas CF, Beecher CW, Fong HH, Farnsworth NR, Kinghorn AD, Mehta RG, Moon RC, Pezzuto JM. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science.1997; 275: 218-220.

[3] Athar M, Back JH, Tang, X, Kim KH, Kopelovich L, Bickers DR, Kim AL. Resveratrol: a review of preclinical studies for human cancer prevention. Toxicology and Applied Pharmacology.2007; 224: 274-283.

[4] Jang JH, Surh YJ. Protective effect of resveratrol on beta-amyloid-induced oxidative PC12 cell death. Free radical Biology & Medicine.2003; 34: 1100-1110.

[5] Zamin LL, Dillenburg-Pilla P, Argenta-Comiran R, Horn AP, Simao F, Nassif M, Gerhardt D, Frozza RL, Salbego C. Protective effect of resveratrol against oxygen-glucose deprivation in organotypic hippocampal slice cultures: Involvement of PI3-K pathway. Neurobiology of Disease.2006; 24: 170-182.

[6] Baur JA, Sinclair DA. Therapeutic potential of resveratrol: the in vivo evidence. Nature Reviews Molecular Cell Biology.2006; 5: 493-506.

[7] Leiro JM, Varela M, Piazzon MC, Arranz JA, Noya M, Lamas J. The anti-inflammatory activity of the polyphenol resveratrol may be partially related to inhibition of tumour necrosis factor-alpha (TNF-alpha) pre-mRNA splicing. Molecular Immunology.2010; 47: 1114-1120.

[8] Filip V, Plockova M, Smidrkal J, Spickova Z, Melzoch K, Schmidt S. Resveratrol and its antioxidant and antimicrobial effectiveness. Food Chemistry.2003; 83: 585-593.

[9] Docherty JJ, McEwen HA, Sweet TJ, Bailey E, Booth TD. Resveratrol inhibition of Propionibacterium acnes. Journal of Antimicrobial Chemotherapy.2007; 59: 1182-1184.

[10] Ferreira WFC, Sousa JCF, Microbiologia Volume 1. LIDEL; 1998.

1233©FORMATEX 2011


[11] Sousa JC. Manual de Antibióticos Antibacterianos. 2sd ed. Porto: Edições Universidade Fernando Pessoa; 2006. [12] Wiley JM, Sherwood LM, Wollverton CJ. Prescott´s Principles of Microbiology. New York, NY: McGraw-Hill Higher

Education; 2009. [13] Overbye KM, Barrett JF. Antibiotics: Where did we go wrong? Drug Discovery.2005; 10: 45-52. [14] Butler MS, Buss AD. Natural products--the future scaffolds for novel antibiotics? Biochemical Pharmacology.2006; 71: 919-

929. [15] Shan B, Cai YZ, Brooks JD, Corke H. Antibacterial properties of Polygonum cuspidatum roots and their major bioactive

constituents. Food Chemistry.2008; 109: 530-537. [16] Tombola F, Campello S, De Luca L, Ruggiero P, Del Giudice G, Papini E, Zoratti M. Plant polyphenols inhibit VacA, a toxin

secreted by the gastric pathogen Helicobacter pylori. FEBS Letters.2003; 543: 184-189. [17] Mahady GB, Pendland SL. Resveratrol inhibits the growth of Helicobacter pylori in vitro. American Journal of

Gastroenterology.2000; 95: 1849-1849. [18] Docherty JJ, Fu MM, Tsai M. Resveratrol selectively inhibits Neisseria gonorrhoeae and Neisseria meningitidis. Journal of

Antimicrobial Chemotherapy.2001; 47: 243-244. [19] Chan MMY. Antimicrobial effect of resveratrol on dermatophytes and bacterial pathogens of the skin. Biochemical

Pharmacology.2002; 63: 99-104. [20] Tegos G, Stermitz FR, Lomovskaya O, Lewis K. Multidrug pump inhibitors uncover remarkable activity of plant

antimicrobials. Antimicrobial Agents and Chemotherapy.2002; 46: 3133-3141. [21] Kim TJ, Weng WL, Silva JL, Jung YS, Marshall D. Identification of natural antimicrobial substances in red muscadine juice

against Cronobacter sakazakii. Journal of Food Science.2010; 75: 150-154. [22] Maddox CE, Laur LM, Tian L. Antibacterial activity of phenolic compounds against the phytopathogen Xylella fastidiosa.

Current Microbiology.2010; 60: 53-58. [23] Paulo L, Ferreira S, Gallardo E, Queiroz JA, Domingues F. Antimicrobial activity and effects of resveratrol on human

pathogenic bacteria. World Journal of Microbiology & Biotechnology.2010; 26: 1533-1538. [24] Boban N, Tonkic M, Budimir D, Modun D, Sutlovic D, Punda-Polic V, Boban M. Antimicrobial Effects of Wine: Separating

the Role of Polyphenols, pH, Ethanol, and Other Wine Components. Journal of Food Science.2010; 75: M322-M326. [25] Boban N, Tonkic M, Modun D, Budimir D, Mudnic I, Sutlovic D, Punda-Polic V, Boban M. Thermally treated wine retains

antibacterial effects to food-born pathogens. Food Control.2010; 21: 1161-1165. [26] Kato E, Tokunaga Y, Sakan F. Stilbenoids isolated from the seeds of Melinjo (Gnetum gnemon L.) and their biological activity.

Journal of Agricultural and Food Chemistry.2009; 57: 2544-2549. [27] Martini S, D'Addario C, Braconi D, Bernardini G, Salvini L, Bonechi C, Figura N, Santucci A, Rossi C. Antibacterial Activity

of Grape Extracts on cagA-Positive and -Negative Helicobacter pylori Clinical Isolates. Journal of Chemotherapy.2009; 21: 507-513.

[28] Pettit RK, Pettit GR, Hamel E, Hogan F, Moser BR, Wolf S, Pon S, Chapuis JC, Schmidt JM. E-Combretastatin and E-resveratrol structural modifications: antimicrobial and cancer cell growth inhibitory beta-E-nitrostyrenes. Bioorganic & Medicinal Chemistry.2009; 17: 6606-6612.

[29] Weber K, Schulz B, Ruhnke M. Resveratrol and its antifungal activity against Candida species. Mycoses.2009: 1-4 [30] Jung HJ, Seu YB, Lee DG. Candicidal action of resveratrol isolated from grapes on human pathogenic yeast C. albicans.

Journal of Microbiology and Biotechnology 2007; 17: 1324-1329. [31] Wang WB, Lai HC, Hsueh PR, Chiou RYY, Lin SB, Liaw SJ. Inhibition of swarming and virulence factor expression in

Proteus mirabilis by resveratrol. Journal of Medical Microbiology.2006; 55: 1313-1321. [32] Chatterjee A, Bagchi D, Yasmin T, Stohs SJ. Antimicrobial effects of antioxidants with and without clarithromycin on

Helicobacter pylori. Molecular and Cellular Biochemistry.2005; 270: 125-130. [33] Jung HJ, Hwang IA, Sung WS, Kang H, Kang BS, Seu YB, Lee DG. Fungicidal effect of resveratrol on human infectious fungi.

Archives of Pharmacal Research.2005; 28: 557-560. [34] Murano A, Morinaga N, Iwamaru Y, Yahiro K, Tagashira M, Moss J, Tanzawa H, Noda M. Acidic conditions enhance

bactericidal effects of sodium bisulfite on Helicobacter pylori. Helicobacter.2005; 10: 132-135. [35] Chatterjee A, Yasmin T, Bagchi D, Stohs SJ. The bactericidal effects of Lactobacillus acidophilus, garcinol and Protykin

compared to clarithromycin, on Helicobacter pylori. Molecular and Cellular Biochemistry.2003; 243: 29-35. [36] Mahady GB, Pendland SL, Chadwick LR. Resveratrol and red wine extracts inhibit the growth of cagA plus strains of

Helicobacter pylori in vitro. American Journal of Gastroenterology.2003; 98: 1440-1441. [37] Pettit GR, Grealish MP, Jung MK, Hamel E, Pettit RK, Chapuis JC, Schmidt JM. Antineoplastic agents. 465. Structural

modification of resveratrol: sodium resverastatin phosphate. Journal of Medicinal Chemistry.2002; 45: 2534-2542. [38] Daroch F, Hoeneisen M, Gonzalez CL, Kawaguchi F, Salgado F, Solar H, Garcia A. In vitro antibacterial activity of Chilean

red wines against Helicobacter pylori. Microbios.2001; 104: 79-85. [39] Marshall BJ.One hundred years of discovery and rediscovery of Helicobacter pylori and its association with peptic ulcer

disease In: Mobley HLT, Mendz GL, Hazell L, eds. Helicobacter pylori: Physiology and genetics. Washington DC: ASM Press; 2001: 19-24.

[40] Alm RA, Ling LS, Moir DT, King BL, Brown ED, Doig PC, Smith DR, Noonan B, Guild BC, deJonge BL, Carmel G, Tummino PJ, Caruso A, Uria-Nickelsen M, Mills DM, Ives C, Gibson R, Merberg D, Mills SD, Jiang Q, Taylor DE, Vovis GF, Trust TJ. Genomic-sequence comparison of two unrelated isolates of the human gastric pathogen Helicobacter pylori. Nature.1999; 397: 176-180.

[41] Tomb JF, White O, Kerlavage AR, Clayton RA, Sutton GG, Fleischmann RD, Ketchum KA, Klenk HP, Gill S, Dougherty BA, Nelson K, Quackenbush J, Zhou L, Kirkness EF, Peterson S, Loftus B, Richardson D, Dodson R, Khalak HG, Glodek A, McKenney K, Fitzegerald LM, Lee N, Adams MD, Hickey EK, Berg DE, Gocayne JD, Utterback TR, Peterson JD, Kelley JM, Cotton MD, Weidman JM, Fujii C, Bowman C, Watthey L, Wallin E, Hayes WS, Borodovsky M, Karp PD, Smith HO, Fraser CM, Venter JC. The complete genome sequence of the gastric pathogen Helicobacter pylori. Nature.1997; 388: 539-547.



[42] McColl KE. Helicobacter pylori 1988-1998. European Journal of Gastroenterology & Hepatology.1999; 11: 13-16. [43] Kusters JG, Van Vliet AH, Kuipers EJ. Pathogenesis of Helicobacter pylori infection. Clinical Microbiology Reviews.2006; 19:

449-490. [44] Azevedo NF, Guimaraes N, Figueiredo C, Keevil CW, Vieira MJ. A new model for the transmission of Helicobacter pylori:

role of environmental reservoirs as gene pools to increase strain diversity. Critical Reviews in Microbiology.2007; 33: 157-169. [45] Montecucco C, Rappuoli R. Living dangerously: How Helicobacter pylori survives in the human stomach. Nature Reviews

Molecular Cell Biology.2001; 2: 457-466. [46] Vale FF, Vitor JMB. Transmission pathway of Helicobacter pylori: Does food play a role in rural and urban areas?

International Journal of Food Microbiology.2010; 138: 1-12. [47] Graham DY. Benefits from Elimination of Helicobacter pylori Infection Include Major Reduction in the Incidence of Peptic-

Ulcer Disease, Gastric-Cancer, and Primary Gastric Lymphoma. Preventive Medicine.1994; 23: 712-716. [48] Blaser MJ, Perez-Perez GI, Kleanthous H, Cover TL, Peek RM, Chyou PH, Stemmermann GN, Nomura A, Infection with

Helicobacter pylori strains possessing cagA is associated with an increased risk of developing adenocarcinoma of the stomach. Cancer Research.1995; 55: 2111-2115.

[49] Censini S, Lange C, Xiang Z, Crabtree JE, Ghiara P, Borodovsky M, Rappuoli R, Covacci A. Cag, a pathogenicity island of Helicobacter pylori, encodes type I-specific and disease-associated virulence factors. Proceedings of the National Academy of Sciences of the United States of America.1996; 93: 14648-14653.

[50] Atherton JC, Cao P, Peek RM, Tummuru MK, Blaser MJ, Cover TL. Mosaicism in vacuolating cytotoxin alleles of Helicobacter pylori. Association of specific vacA types with cytotoxin production and peptic ulceration. The Journal of Biological Chemistry.1995; 270: 17771-17777.

[51] Rhead JL, Letley DP, Mohammadi M, Hussein N, Mohagheghi MA, Eshagh Hosseini M, Atherton JC. A new Helicobacter pylori vacuolating cytotoxin determinant, the intermediate region, is associated with gastric cancer. Gastroenterology.2007; 133: 926-936.

[52] McClain MS, Cao P, Iwamoto H, Vinion-Dubiel AD, Szabo G, Shao Z, Cover TL. A 12-amino-acid segment, present in type s2 but not type s1 Helicobacter pylori VacA proteins, abolishes cytotoxin activity and alters membrane channel formation. Journal of Bacteriology.2001; 183: 6499-6508.

[53] Mobley HLT, Cortesia MJ, Rosenthal LE, Jones BD. Characterization of Urease from Campylobacter pylori. Journal of Clinical Microbiology.1988; 26: 831-836.

[54] Nagata K, Satoh H, Iwahi T, Shimoyama T, Tamura T. Potent inhibitory action of the gastric proton pump inhibitor lansoprazole against urease activity of Helicobacter pylori: unique action selective for H. pylori cells. Antimicrobial Agents and Chemotherapy.1993; 37: 769-774.

[55] Brenner H, Rothenbacher D, Bode G, Adler G. Inverse graded relation between alcohol consumption and active infection with Helicobacter pylori. American Journal of Epidemiology.1999; 149: 571-576.

[56] Ruggiero P, Rossi G, Tombola F, Pancotto L, Lauretti L, Del Giudice G, Zoratti M. Red wine and green tea reduce H pylori- or vacA-induced gastritis in a mouse model. World Journal of Gastroenterology.2007; 13: 349-354.

[57] Bertelli AAA, Das DK. Grapes, Wines, Resveratrol, and Heart Health. Journal of Cardiovascular Pharmacology.2009; 54: 468-476.

[58] Anastasiadi M, Pratsinis H, Kletsas D, Skaltsounis AL, Haroutounian SA. Bioactive non-coloured polyphenols content of grapes, wines and vinification by-products: Evaluation of the antioxidant activities of their extracts. Food Research International.2010; 43: 805-813.

[59] Paulo L, Oleastro M, Gallardo E, Queiroz JA, Domingues F. Anti-Helicobacter pylori and urease inhibitory activities of resveratrol and red wine. Food Research International.2011; 44: 964-969.

[60] Lee SY, Shin YW, Hahm KB. Phytoceuticals: Mighty but ignored weapons against Helicobacter pylori infection. Journal of Digestive Diseases.2008; 9: 129-139.

[61] Ralhan R, Pandey MK, Aggarwal BB. Nuclear factor-kappa B links carcinogenic and chemopreventive agents. Frontiers in Bioscience (Scholar Edition).2009; 1: 45-60.

[62] Zaidi SF, Ahmed K, Yamamoto T, Kondo T, Usmanghani K, Kadowaki M, Sugiyama T. Effect of resveratrol on Helicobacter pylori-induced interleukin-8 secretion, reactive oxygen species generation and morphological changes in human gastric epithelial cells. Biological & Pharmaceutical Bulletin.2009; 32: 1931-1935.

1235©FORMATEX 2011


Documents

Antimicrobial properties of resveratrol: a review