Antimicrobial properties of resveratrol: a review -...
Transcript of 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
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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
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Sample Strain Methods Reference
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
Staphylococcus aureus ATCC 29213
Streptococcus pneumoniae ATCC 6303
Enterococcus faecalis ATCC 29212
Micrococcus luteus Presque Isle 456
Stenotrophomonas maltophilia ATCC 13637
Escherichia coli ATCC 25922
Enterobacter cloacae ATCC 13047
Neisseria gonorrhoeae ATCC 49226
Resveratrol
Candida albicans ATCC 90028
Agar Dilution [29]
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
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
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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
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
Staphylococcus aureus
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
Staphylococcus aureus ATCC 29213
Microdilution [19]
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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Sample Strain Methods Reference
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
Staphylococcus aureus
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].
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Fig. 2- Plot oKnowledge se
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2.3
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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).
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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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