Beyond nutrition: health-promoting foods by quorum-sensing inhibition
2012; Future Medicine; Volume: 7; Issue: 9 Linguagem: Inglês
10.2217/fmb.12.84
ISSN1746-0921
Autores Tópico(s)Probiotics and Fermented Foods
ResumoFuture MicrobiologyVol. 7, No. 9 EditorialFree AccessBeyond nutrition: health-promoting foods by quorum-sensing inhibitionMichael GivskovMichael GivskovCentre for Antimicrobial Research, Department of International Health, Immunology & Microbiology, University of Copenhagen, Copenhagen, Denmark and Singapore Center of Environmental Life Science, Nanyang Technological University, Singapore. Published Online:6 Sep 2012https://doi.org/10.2217/fmb.12.84AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit Keywords: biofilm dispersalbiofilmsc-di-GMPfunctional foodgarlicherbsimmune systemnatural compoundsquorum sensing'Good food' and 'good health' are key ingredients of the 'good life' and we live with an increasing life expectancy. Despite technological and medical progression, debilitating and life-threatening infections are returning as a serious threat in well-developed countries. What seems to so significantly affect our sensitivity to pathogens? Western societies are currently going through a multitude of changes, perhaps the most pronounced being the increase in the number of elderly, immunocompromised and hospitalized people. Such citizens are particularly susceptible to chronic infections, many of which are caused by Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus. In my own little country, Denmark (population size ∼5.6 million), approximately 100,000 people (corresponds to 10% of hospitalized patients) acquire infections in connection with the use of medical devices such as arteriovenous shunts, pacemakers, urinary and other types of catheters, orthopedic devices and mechanical heart valves. Skin ulcers that develop into chronic wounds are also a significant and partly neglected problem, which affects patients with impaired blood circulation, in particular those with Type 2 diabetes. It is assumed that approximately 50,000 citizens suffer from wounds that require special treatment and medical attention because of bacterial infections. Finally, a more specialized patient group are the cystic fibrosis sufferers (in Denmark less than 1000) battling lifelong P. aeruginosa infection. Taken together, infections are considered to impose a DKK 4 billion (US$665 million) load on the total healthcare budget of approximately DKK 90 billion ($15 billion). It is an important socioeconomic burden, which includes patient suffering, lost employment and reduced life quality.A major problem for the clinicians is that the biofilm lifestyle dominates chronic bacterial infections. Chronic bacterial infections share similar characteristics: they are hard to diagnose, they resist the activities of the host immune system and they are difficult to eradicate with present day's armories of antibiotics. To meet this hardly sustainable situation, new antibiofilm measures must therefore be identified which efficiently decrease the biofilm-forming capabilities and persistence of infectious bacteria.The majority of antimicrobials target a limited number of basal life processes in bacteria, such as DNA and RNA replication, protein biosynthesis and cell wall synthesis. These were the 'low-hanging fruits' for traditional methods of antibiotic discovery. Although antibiotics have saved millions of lives, they strongly promote development of resistant bacterial variants by their mode of action. The prospect of a future post-antibiotic era with mortality reminiscent of the pre-antibiotic days urgently calls for novel targets and innovative approaches to the control and cure of infectious diseases. Cell-to-cell communication (denoted quorum-sensing, or QS) controls expression of virulence and shielding against (or resistance to) the phagocytic cells of the innate immune system in already-formed biofilms [1–3], whereas internal, second messenger signaling, referred to as cyclic diguanosine monophosphate (c-di-GMP) signaling, controls initiation, building and dissolution of the biofilm [4,5]. Virulence factors that function as 'immuneshields' are probably a common phenomenon and in P. aeruginosa the shield is built by the powerful detergent rhamnolipid, a compound that shields the microbe from normally antimicrobial (phagocytic) white blood cells. Over the years, we have undertaken a series of comprehensive investigations of natural compounds targeting bacterial QS systems, and it further strengthens previous proof-of-concept research we conducted on the potential of compounds which block communication among the pathogens in contrast to simply killing bacteria [2], as conventional antibiotics do. Another approach to deal with these multidrug-resistant bacteria would involve chemistry that locks bacteria in the free-living (planktonic) mode or alternatively causes dispersal of already-made biofilms. Away from this protective state, bacterial cells are generally hundreds-to-thousand-fold more sensitive to the action of the immune system and conventional antimicrobials including antibiotics. In conclusion, blocking the line of command between biofilm bacteria tears down the biofilm shielding and actually reinstates proper antimicrobial action of the immune system. Future intervention regimes could therefore be built on these biofilm regulating principles in combination with conventional antibiotics for example. Such chemotherapeutic approaches may postpone or minimize development of resistance to the conventional antibiotics.Since the nature of chronic infections is often opportunistic and primarily involves weakened and immunocompromised citizens, it is an appealing hypothesis that susceptibility is influenced by particular 'lifestyles' with similarities to conditions that promote development of heart diseases, Type 2 diabetes and certain cancers. Along this line, it may be that 'resistance' or 'susceptibility' to chronic infections to a certain extent is influenced by the diet and in particular by certain food components. Probably the best such known herb is garlic which has been used medicinally for thousands of years. In relation to its content of small molecule chemistry, garlic not only has antibacterial properties; it has antiviral, antifungal and antiprotozoal properties as well, and it has beneficial effects on the cardiovascular and immune systems (see [6] for comprehensive review). Several years ago we found that crude extracts of garlic promote a rapid clearing of pulmonary P. aeruginosa infections in mice [7]. This encouraged us to screen 69 common food products and plants for QS inhibition. As the most promising, my research team subsequently identified iberin from horseradish and ajoene from garlic as the pure active compounds [8,9]. In-depth gene expression analysis revealed that the two compounds seem to hit different targets but they both reduced expression of key QS controlled virulence factors in P. aeruginosa, including production of the rhamnolipid shield. Ajoeneis is the major component in a cocktail of QS-inhibitory sulfur-containing compounds, which is produced when garlic is crushed. My team found that chemically synthesized ajoene inhibited expression of 11 virulence genes that are controlled by QS, key genes that are regarded as crucial for the ability of P. aeruginosa to cause disease. Interestingly, garlic extract inhibited three times as many known P. aeruginosa QS genes [7] and, taken together with multiple chromatographic analyses, the most reasonable explanation to this discrepancy was that garlic (when crushed) contains a multitude of QS inhibitory compounds. The fact is that we simply did not succeed in purification of the multiple, hydrophilic components of the mixed QS inhibitor cocktail. However, the chemically synthesized ajone cleared P. aeruginosa infection in our pulmonary mouse model and therefore worked well as an antimicrobial. On the other hand, we found no significant difference in bacterial clearance between iberin-treated and nontreated mouse models. The reason for iberin's apparent deficiency as a pure chemical may be attributed to its reactive isothiocyanate group, which will almost completely neutralize its effect in vivo. Along this line, we also found that that when ajoene was purified to 100%, it lost activity quite abruptly. Surprisingly, the reason for itsbio activity as chemically synthesized compound (without extensive purification) could be explained by the presence of small amounts of additional chemistry derived from the major compound ajoene itself; a situation that is likely to be reminiscent of the accompanying chemistry found in crushed garlic. It is important to note that QS inhibitors do not kill target bacteria, but they weaken their biofilms to the exposure of conventional antibiotics and the immune system. Along this line, by combining ajoene treatments with the antibiotic tobramycin, it was possible to kill over 90% of bacteria living in a biofilm in contrast to tobramycin treatment alone, which killed less than 10% [10]. It also rescued the white blood cells from destruction on the otherwise established phagocytic shield [9].So where does this take us in terms of particular diets that would aim at minimizing infections? In my experience, it is unlikely that any natural food source has biologically relevant amounts of QS inhibitors to cure already-established infections. For example, to produce the eradication effect we obtained previously with garlic extract on infected mice would for an adult human require the daily intake of 50 bulbs of garlic for several days. We can all imagine that this would generate a multitude of unwanted side effects. What is particularly interesting is that the combination of QS inhibitors and other antimicrobials (in this way accessing a number of antimicrobial targets) including those compounds that may function to stabilize their biological activities may produce synergistic effects that would reduce the otherwise higher concentrations that are required of each of the pure compounds. To scientifically prove this, it would need purification/synthesis of a multitude of diverse chemical compounds in order to generate reproducible results in our mouse models. In academia, funds are limited and restricted, hence we have been unable to address this in a scientific way, and we are left to speculate.There is no doubt, however, that small-molecule chemistry from foods is an attractive source for antimicrobials. Drugs can subsequently be developed based on their natural chemistry. I do believe, however, that food sources may offer preventive effects. For example, we found that beansprouts, chamomile, carrots, lemongrass, chili habanero, yellow peppers and beeswax do show QS inhibition activities. We identified the first natural QS inhibitors in seaweed [11] as antibiofilm measures and this may extend to edible variants that are key elements in everyday Japanese cuisine. Most likely, by combining the right food sources, synergistic actions may be obtained. Should disposed people then become vegetarians? In my mind, there is little doubt that animal protein sources promote good overall nutrition. But we do not find QS inhibitors in meat! So, beyond the obvious basic nutritional requirements, if one puts effort into an everyday green, multicomponent, ingredient-rich diet (including supplementary constituents such as functional foods), it may actually offer a natural prophylaxis, and for the unwell in particular, a reduced risk of acquiring chronic infections. This is further support of the 'healthy preference' which also provides high vitamin and mineral content in low-calorie count. When citizens make unhealthy food choices a habit, they will likely suffer health consequences. Unfortunately, the diet of the developed world is dangerously high in fat, cholesterol, salt and sugar. It accompanies a rise in chronic diseases with dietary causes, such as Type 2 diabetes, which in turn disposes the patient to developing, for example, chronic infected wounds. The central finding that certain healthy foods contain chemistry that reinstates proper function of the immune system should urge scientific research with the ultimate aim of developing highly efficient antimicrobial diets.Financial & competing interests disclosureThis work has received financial support from the German Mukoviszidose Institut and from the Danish Strategic Research Council. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.References1 Bjarnsholt T, van Gennip M, Jakobsen TH, Christensen LD, Jensen PO, Givskov M. In vitro screens for quorum sensing inhibitors and in vivo confirmation of their effect. Nat. Protoc.5(2),282–293 (2010).Crossref, Medline, CAS, Google Scholar2 Hentzer M, Wu H, Andersen JB et al. Attenuation of Pseudomonas aeruginosa virulence by quorum sensing inhibitors. EMBO J.22(15),3803–3815 (2003).Crossref, Medline, CAS, Google Scholar3 Jensen PØ, Bjarnsholt T, Phipps R et al. Rapid necrotic killing of polymorphonuclear leukocytes is caused by quorum-sensing-controlled production of rhamnolipid by Pseudomonas aeruginosa. Microbiology153(Pt 5),1329–1338 (2007).Crossref, Medline, CAS, Google Scholar4 Gjermansen M, Ragas P, Sternberg C, Molin S, Tolker-Nielsen T. Characterization of starvation-induced dispersion in Pseudomonas putida biofilms. Environ. Microbiol.7(6),894–906 (2005).Crossref, Medline, CAS, Google Scholar5 Gjermansen M, Ragas P, Tolker-Nielsen T. Proteins with GGDEF and EAL domains regulate Pseudomonas putida biofilm formation and dispersal. FEMS Microbiol. Lett.265(2),215–224 (2006).Crossref, Medline, CAS, Google Scholar6 Block E. Garlic and Other Alliums: The Lore and the Science Publisher. Royal Society of Chemistry, Cambridge, UK (2010).Google Scholar7 Bjarnsholt T, Jensen PØ, Rasmussen TB et al. Garlic which blocks the Pseudomonas aeruginosa communication systems, promotes rapid clearing of pulmonary Pseudomonas aeruginosa infections. Microbiology151(Pt 12),3873–3880 (2005).Crossref, Medline, CAS, Google Scholar8 Jakobsen TH, van Gennip M, Phipps RK et al. Ajoene, a sulfur-rich molecule from garlic, inhibits genes controlled by quorum sensing. Antimicrob. Agents Chemother.56(5),2314–2325 (2012).Crossref, Medline, CAS, Google Scholar9 Jakobsen TH, Bragason SK, Phipps RK et al. Food as a source for quorum sensing inhibitors: iberin from horseradish revealed as a quorum sensing inhibitor of Pseudomonas aeruginosa. Appl. Environ. Microbiol.78(7),2410–2421 (2012).Crossref, Medline, CAS, Google Scholar10 Christensen LD, van Gennip M, Jakobsen TH et al. Synergistic antibacterial efficacy of early combination treatment with tobramycin and quorum-sensing inhibitors against Pseudomonas aeruginosa in an intraperitoneal foreign-body infection mouse model. J. Antimicrob. Chemother.67(5),1198–1206 (2012).Crossref, Medline, CAS, Google Scholar11 Givskov M, de Nys R, Manefield M et al. Eukaryotic interference with homoserine lactone mediated prokaryotic signalling. J. Bacteriol.178,6618–6622 (1996).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetailsCited ByComparative Assessment of Phenolic Composition Profile and Biological Activities of Green Extract and Conventional Extracts of Salvia Sclarea1 January 2023 | SSRN Electronic Journal, Vol. 10Targeting quorum sensing and biofilm formation in the control of Vibrio harveyi infections in Penaeus vannamei8 July 2022 | Aquaculture Research, Vol. 53, No. 14Piper betle L. leaf extracts inhibit quorum sensing of shrimp pathogen Vibrio harveyi and protect Penaeus vannamei postlarvae against bacterial infectionAquaculture, Vol. 547Antivirulence Activity of a Dietary Phytochemical: Hibiscus Acid Isolated from Hibiscus sabdariffa L. Reduces the Virulence of Pseudomonas aeruginosa in a Mouse Infection ModelJournal of Medicinal Food, Vol. 24, No. 9The New Antibacterial Properties of the Plants: Quo vadis Studies of Anti-virulence Phytochemicals?7 May 2021 | Frontiers in Microbiology, Vol. 12Anti-quorum sensing and antibiofilm potential of 1,8-cineole derived from Musa paradisiaca against Pseudomonas aeruginosa strain PAO119 March 2021 | World Journal of Microbiology and Biotechnology, Vol. 37, No. 4Evaluation of quorum-sensing inhibitory effects of extracts of three traditional medicine plants with known antibacterial propertiesNew Microbes and New Infections, Vol. 38Green tea (Camellia sinensis) extract inhibits biofilm formation in acyl homoserine lactone-producing, antibiotic-resistant Morganella morganii isolated from Pasig River, PhilippinesHeliyon, Vol. 6, No. 10The Role of Drug Repurposing in the Development of Novel Antimicrobial Drugs: Non-Antibiotic Pharmacological Agents as Quorum Sensing-Inhibitors17 December 2019 | Antibiotics, Vol. 8, No. 4Inhibition of Quorum Sensing and Virulence in Serratia marcescens by Hordenine4 January 2019 | Journal of Agricultural and Food Chemistry, Vol. 67, No. 3Vanillic acid from Actinidia deliciosa impedes virulence in Serratia marcescens by affecting S-layer, flagellin and fatty acid biosynthesis proteins27 November 2017 | Scientific Reports, Vol. 7, No. 1Quorum Quenching and Microbial Control through Phenolic Extract of Eugenia Uniflora Fruits7 September 2016 | Journal of Food Science, Vol. 81, No. 10Anti-quorum sensing activity of phenolic extract from Eugenia brasiliensis (Brazilian cherry)29 April 2016 | Food Science and Technology, Vol. 36, No. 22-Furaldehyde diethyl acetal from tender coconut water ( Cocos nucifera ) attenuates biofilm formation and quorum sensing-mediated virulence of Chromobacterium violaceum and Pseudomonas aeruginosa16 November 2015 | Biofouling, Vol. 31, No. 9-10How microbes communicate in food: a review of signaling molecules and their impact on food qualityCurrent Opinion in Food Science, Vol. 2Effect of certain natural products and organic solvents on quorum sensing in Chromobacterium violaceumAsian Pacific Journal of Tropical Medicine, Vol. 7Emerging frontiers in detection and control of bacterial biofilmsCurrent Opinion in Biotechnology, Vol. 26Inhibition of quorum sensing in Chromobacterium violaceum by Syzygium cumini L. and Pimenta dioica L.Asian Pacific Journal of Tropical Biomedicine, Vol. 3, No. 12 Vol. 7, No. 9 Follow us on social media for the latest updates Metrics History Published online 6 September 2012 Published in print September 2012 Information© Future Medicine LtdKeywordsbiofilm dispersalbiofilmsc-di-GMPfunctional foodgarlicherbsimmune systemnatural compoundsquorum sensingFinancial & competing interests disclosureThis work has received financial support from the German Mukoviszidose Institut and from the Danish Strategic Research Council. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download
Referência(s)