The Canadian Government Think-tank Policy Horizons Canada published a report in June 2024 that caught everyone’s attention. Its ‘Disruptions on the Horizon Report‘ posited rather ominously:
‘Antimicrobial resistance (AMR) has reached critical levels. AMR is the leading cause of death globally, and food systems are disrupted as it is more expensive for producers to ensure animal or plant health.’
Whilst some may consider this is overstating the risk a little, the report highlights a critical issue: Combating antimicrobial resistance (AMR) is a vital issue for the future wellbeing of humanity.
The global rise in antibiotic resistance poses a significant threat, diminishing the efficacy of common antibiotics against widespread bacterial infections. The 2022 Global Antimicrobial Resistance and Use Surveillance System (GLASS) report highlights alarming resistance rates among prevalent bacterial pathogens. Median reported rates in 76 countries of 42% for third-generation cephalosporin-resistant E. coli and 35% for methicillin-resistant Staphylococcus aureus are a major concern. For urinary tract infections caused by E. coli, 1 in 5 cases exhibited reduced susceptibility to standard antibiotics like ampicillin, co-trimoxazole, and fluoroquinolones in 2020. This is making it harder to effectively treat common infections. (World Health Organization 2023)
The issue does not just impact human medical treatment, but impacts food systems, as it is becoming more costly for producers to maintain the health of animals and plants.
In an effort to tackle this emergency, scientists and public health experts are considering new strategies. They are looking at the potential benefits of polyphenols.
Polyphenols are found in many plant-based foods. They show exciting antimicrobial and anti-infective traits. These properties could play a key role in addressing the challenge of AMR.
Dealing with this issue will require a united front globally. This includes launching public awareness campaigns, fostering research collaborations, and implementing policy interventions. A comprehensive effort is vital for combating antimicrobial resistance. It’s also key for preserving the effectiveness of current medicines.
Key Takeaways
- Polyphenols, such as resveratrol, EGCG, quercetin, curcumin, and ellagic acid, show promise in combating antimicrobial resistance.
- These compounds can enhance antibiotic action, inhibit AMR development, and disrupt biofilm formation.
- Polyphenols work through various mechanisms, including epigenetic modifications and cell signaling pathways.
- Their antimicrobial effects make them valuable in the fight against drug-resistant pathogens.
Preclinical testing and extract standardization are crucial in researching their antimicrobial properties. - Including polyphenols in comprehensive strategies can contribute to combating AMR globally.
Polyphenols offer a natural alternative and/or synergistic supplement to traditional antibiotics in combating antimicrobial resistance.
Introduction
Combating Antimicrobial Resistance (AMR) has emerged as a pressing global health imperative. The proliferation of antibiotic-resistant bacteria endangers public health worldwide. This crisis has propelled natural compounds, notably polyphenols, into the spotlight. They offer new prospects for battling AMR either on their own or together with standard therapies. Polyphenols come from plants and exhibit various valuable qualities, including their known antimicrobial, antioxidant, and anti-inflammatory effects.
Polyphenols stand out as the leading stars in the realm of pharmacological therapeutics, showcasing their prowess as primary components in our daily dietary intake [10]. Aside from being an essential antioxidant agent, this group of compounds has been widely reported to possess anti-allergic, antihypertensive, anti-inflammatory, anticancer, antiviral, and antimicrobial potencies [11] of which most of these biological activities are consequences of the antioxidative effect of this class of organic molecules. (Rudrapel 2024)
Just what are of Polyphenols?
Polyphenols are secondary metabolites present in fruits, vegetables, grains, and herbs. These compounds feature multiple phenol groups, granting them their diverse biological roles. Their unique chemical structure is the key to their wide-ranging beneficial activities. Scientists are particularly interested in polyphenols because of their potential to support better use of antimicrobials, fight off resistance, and offer alternative means of controlling infections.
Which Foods Contain Polyphenols?
There is a wealth of polyphenol-rich foods, offering hope in our battle against antimicrobial resistance. For instance, there’s green tea, berries like blueberries, raspberries, and cranberries, as well as pomegranates. Additionally, dark chocolate, red wine, and various herbs and spices – think turmeric, rosemary, and thyme – fall in this category. The ample diversity of these foods provides an encouraging path towards finding natural approaches that could help check AMR and bolster our fight against infections.
Here are some or the Key Antimicrobial Polyphenols!
In the realm of polyphenol research for combating antimicrobial resistance and addressing other health challenges, several compounds have shown promising antimicrobial properties.
Here are some of the most hopeful polyphenol candidates currently being researched:
Resveratrol:
Source:** Found in grapes, red wine, and berries.
Benefits:** Exhibits antimicrobial, anti-inflammatory, and antioxidant properties.
Potential:** Effective against a range of bacterial and fungal pathogens, with studies showing potential in combating AMR.
Epigallocatechin Gallate (EGCG):
Source:** Main polyphenol in green tea.
Benefits:** Strong antioxidant and antimicrobial properties.
Potential:** Has shown activity against various drug-resistant bacteria and has been explored for its role in combating AMR.
Quercetin:
Source:** Abundant in fruits, vegetables, (e.g. onions apples and berries) and grains.
Benefits:** Anti-inflammatory, antioxidant, and antibacterial properties.
Potential:** Being investigated for its antimicrobial effects against resistant bacteria, including its ability to enhance the efficacy of antibiotics.
Curcumin:
Source:** Main compound in turmeric.
Benefits:** Anti-inflammatory, antioxidant, and antimicrobial properties.
Potential:** Studies suggest it may help overcome antibiotic resistance in bacteria and combat various infections.
Ellagic Acid:
Source:** Found in berries, pomegranates, and nuts.
Benefits:** Antioxidant and antimicrobial properties.
Potential:** Research indicates its efficacy against drug-resistant bacteria and its role in combating biofilm formation.
Apigenin:
Source:** Present in parsley, celery, and chamomile tea.
Benefits:** Anti-inflammatory and antimicrobial properties.
Potential:** Studied for its antibacterial effects against drug-resistant strains and potential as an adjunct to conventional antibiotics.
Catechins:
Source:** Found in tea, cocoa, and fruits.
Benefits:** Antioxidant and antimicrobial properties.
Potential:** Particularly epicatechin and epigallocatechin have shown promise in combating drug-resistant bacteria and biofilms.
Kaempferol:
Source:** Present in various fruits and vegetables (eg kale spinach and broccoli).
Benefits:** Anti-inflammatory and antimicrobial properties.
Potential:** Investigated for its ability to inhibit bacterial growth, including drug-resistant strains.
Research continues to explore the efficacy, mechanisms of action, and potential synergies of these and other polyphenols in tackling antimicrobial resistance and improving health outcomes. Their diverse properties make them valuable candidates in the quest to combat drug-resistant pathogens and enhance global health.
Polyphenols – Subclass, Category and Compounds (adapted from Bo et al 2019)
| Subclass | Category | Compounds |
|---|---|---|
| Flavonoids | Flavanols | Epicatechin, Catechin, Epigallocatechin-gallate |
| Flavanones | Hesperidin, Naringenin, Eriodictyol | |
| Flavones | Apigenin, Luteolin, Tangeritin, Chrysin | |
| Isoflavones | Genistein, Daidzein | |
| Flavonols | Kaempferol, Myrestin, Quercitin | |
| Anthocyanins | Cyanidin, Delphinidin, Malvedin, Pelargonidin | |
| Phenolic Acids | Hydroxybenzoic acid | Protocatechuic acid, Gallic acid, Vanillic acid, Ellagic acid, Salicylic acid |
| Hydroxycinnamic acid | Caffeic acid, Ferulic acid, Sinapic acid, Chlorogenic acid, p-Coumaric acid, Quinic acid | |
| Lignans | Secoisolariciresinol, Pinoresinol, Lariciresinol, Syringaresinol, Matairesinol, Hydroxymatairesinol, Sesamin | |
| Stilbenes | Resveratrol, Pterostilbene | |
| Coumarins | Curcumin |
Which Plant Sources have the most Quercetin and Kaempferol?
| Source | Quercetin | Kaempferol |
|---|---|---|
| Food | mg/100 g fresh weight | |
| Apples | 4.01 | 0.14 |
| Asparagus | 14.0 | 1.40 |
| Broccoli | 13.7 | 7.20 |
| Chili pepper | 32.6 | – |
| Chinese cabbage | – | 22.5 |
| Kale | 22.6 | 47.0 |
| Leeks | 0.9 | 2.67 |
| Lettuce | 14.7 | 0.84 |
| Onions | 45.0 | 4.50 |
| Spinach | 27.2 | 55.0 |
| Chives | 10.4 | 12.5 |
| Dill | 79.0 | 40.0 |
| Fennel leaves | 46.8 | 6.50 |
| Oregano | 42.0 | – |
| Blueberry | 14.6 | 3.17 |
| Cherry | 17.4 | 5.14 |
| Cranberry | 25.0 | 0.21 |
| Wild leeks (whole) [17] | 8.36 | 5.31 |
| Beverage | mg/100 ml | |
| Black tea | 2.50 | 1.70 |
| Red wine | 3.16 | 0.25 |
Sources: Phenol-Explorer and USDA (United States Department of Agriculture) Database for the Flavonoid Content of Selected Foods.
A Graphic of Dietary Polyphenols
(from Rudrapel 2024)
How do Polyphenols Work?
Polyphenols can exert their effects through various mechanisms, including epigenetic modifications, modulation of cell signaling cascades, and other pathways. Here is an overview of how polyphenols work at the molecular level:
1. Epigenetic Modulation:
DNA Methylation: Some polyphenols can inhibit DNA methyltransferases, enzymes responsible for DNA methylation, thereby influencing gene expression patterns.
Histone Modification:** Polyphenols can alter histone acetylation and methylation patterns, impacting chromatin structure and gene transcription regulation.
MicroRNA Regulation:** Certain polyphenols can modulate microRNA expression, affecting post-transcriptional gene regulation.
2. Cell Signaling Pathways:
MAPK Pathway: Polyphenols may activate or inhibit MAPK pathways, influencing processes like cell growth, differentiation, and inflammation.- **PI3K/Akt Pathway:** Polyphenols can regulate the PI3K/Akt pathway, which plays a role in cell survival, growth, and metabolism.
NF-κB Pathway: Some polyphenols exhibit anti-inflammatory effects by suppressing NF-κB signaling, a key pathway in inflammation and immunity.
Wnt/β-Catenin Pathway: Polyphenols may affect the Wnt/β-catenin pathway involved in cell proliferation and differentiation.
3. Antioxidant Activity:
Polyphenols are well-known for their antioxidant properties, scavenging free radicals and reducing oxidative stress, which can impact cell signaling pathways and gene expression.
4. Anti-Inflammatory Effects:
Many polyphenols can modulate inflammatory pathways, such as NF-κB and MAPK signaling, leading to reduced inflammation and associated downstream effects.
5. Mitochondrial Function:
Polyphenols have been shown to influence mitochondrial function, including ATP production, reactive oxygen species (ROS) generation, and mitochondrial membrane potential.
6. Cell Cycle Regulation:
Some polyphenols can impact cell cycle progression, cell proliferation, and apoptosis through regulation of cell cycle-related proteins and signaling pathways.
7. Anti-Microbial Effects:
Polyphenols exhibit direct antimicrobial effects by disrupting bacterial cell membranes, inhibiting enzyme activity, and interfering with bacterial metabolism.
Polyphenols enhance antibiotic action
Recent research points to the benefits of using cranberry extracts as a natural substitute for antibiotics. These compounds can slow down AMR. They also aid antibiotics in working more effectively and restore their power against resistant bacteria, like Staphylococcus aureus.
…some natural polyphenols, aside from direct antibacterial activity, exert a synergistic effect when combined with common chemotherapeutics. Many studies have proved that in synergy with antibiotics plant flavonoids pose a promising alternative for therapeutic strategies against drug resistant bacteria. (Miklasinska-Majdanik 2019)
Polyphenols inhibiting AMR development
Polyphenols are key in preventing the rise of AMR. They target various functions in bacterial cells, which reduces the chances of drug resistance developing. This makes them an important part of efforts to protect the effectiveness of antimicrobials.
Polyphenols disrupting biofilm formation
Besides their role in fighting AMR, polyphenols can break down microbial biofilms. These biofilms are tough to eliminate with standard treatments. By destroying biofilms, polyphenols help control infections better and can lead to improved patient recovery.
Candida albicans is the primary candidiasis-causing fungal pathogen in humans, and one of its most important virulence factors is the ability to form biofilms. Moreover, these biofilms are often resistant to antifungal agents, so there is a need to develop alternative elimination strategies and therapeutic agents for such infections. The antifungal activity of resveratrol, a phytoalexin polyphenolic compound, impairs the morphological transition of C. albicans under various hypha-inducing conditions and inhibits growth of the yeast-form and mycelia. …. The present results indicate that resveratrol has the potential to serve as an anti-Candida treatment and preventive tool which functions by inhibiting existing or under-forming C. albicans biofilms. (Okamoto-Shibayama 2021)
Preclinical Testing and Future Scope
Rigid preclinical testing and extract standardization are key as researchers delve into polyphenols’ antimicrobial prowess. Miklasińska et al. and Babu et al. have shown how cranberry extracts, such as Cysticare and Cysticelna, boost the actions of antibiotics like ciprofloxacin and cefuroxime against MRSA strains. They also enhance efficacy against foes like Clostridium.
Future Prospects:
1. **Alternative Therapeutic Approach:** Polyphenols offer a natural and potentially effective alternative to traditional antibiotics, especially in cases where antibiotic resistance limits treatment options.
2. **Bioactive Properties:** Polyphenols exhibit diverse biological activities, including antimicrobial, anti-inflammatory, and immunomodulatory effects, making them valuable in addressing infections and inflammatory conditions.
3. **Combating AMR:** By targeting resistant bacteria through mechanisms that differ from conventional antibiotics, polyphenols may help overcome resistance and enhance the efficacy of existing treatment options.
4. **Synergistic Effects:** Combinations of polyphenols with traditional antibiotics or other antimicrobial agents could lead to synergistic effects, improving therapeutic outcomes against multidrug-resistant pathogens. (See next Section for more)
5. **Preventive Health Benefits:** The consumption of polyphenol-rich foods and supplements may not only help combat bacterial infections but also offer preventive health benefits due to their antioxidant and anti-inflammatory properties. (See Below for more)
Synergistic Effects
Antistaphylococcal properties of flavonols, flavanols and phenolic acids. (From Miklasinska-Majdanik 2019)
| Phenolic Compound | Proposed Mechanism of Action | Examined Strains | Synergism with Antibiotics | References |
|---|---|---|---|---|
| Flavolons | ||||
| Galangin | a | S. aureus NCTC 6571 | Penicillin G | [38,41] |
| Morin | b | S. aureus clinical strains | – | [42] |
| Quercetin | c | MRSA clinical strains | Rifampicin Ciprofloxacin |
[43,44,45] |
| Kaempferol | c | MRSA clinical strains | Rifampicin Ciprofloxacin Fluoroquinolone |
[43,44,45,46] |
| Flavanols and Derivatives | ||||
| (−)-Epigallocatechin gallate | b,d | MRSA and MSSA clinical and standard strains | Oxacillin Ampicillin/Sulbactam Penicillin Imipenem Panipenem Meropenem Tetracyclin Oxytetracycline |
[47,48,49,50,51,52,53] |
| (+)-catechin acyl derivatives | a | MRSA clinical strains | – | [40] |
| Epicatechin gallate | a,e | MRSA clinical strains | β-lactams Ampicillin Ampicillin/Sulbactam Cefazolin Cefepime Imipenem/Cilastatin |
[4,37,54] |
| 3-O-decyl-(+)-catechin | a | MRSA and MSSA clinical strains | – | [55] |
| (+)-catechin | e | MRSA clinical strains | Ampicillin Ampicillin/Sulbactam Cefazolin Cefepime Imipenem/Cilastatin |
[4] |
| Catechin hydrate | nk | MRSA and MSSA clinical and standard strains | Clindamycin Erythromycin |
[18] |
| Phenolic Acids and Derivatives | ||||
| Ferulic acid | a | S. aureus ATCC 6538 | – | [56] |
| Coumaric acid | a | S. aureus ATCC 6538 | – | [56] |
| Chlorogenic acid | a | S. aureus ATCC 6538 | – | [56] |
| Protocatechuic acid ethyl ester |
nk | MRSA and MSSA clinical and standard strains | Clindamycin | [5] |
| Caffeic acid | a | MRSA and MSSA clinical and standard strains | Clindamycin Erythromycin Cefoxitin |
[16,57,58,59] |
a—interaction with a cytoplasmic membrane,
b—influence on the staphylococcal virulence factors,
c—inhibition of bacterial topoisomerases activity,
d—direct action on the bacterial cell wall,
e—inhibition of bacterial gene expression,
nk—not known.
Preventation is better than Cure.
Incorporating polyphenols in both food and supplement form plays a crucial role in promoting preventative health benefits in the context of antimicrobial resistance (AMR). Polyphenols, derived from various plant-based sources like fruits, vegetables, and teas, possess potent antioxidant and antimicrobial properties that can help fortify the body’s natural defenses against infections.
By integrating polyphenol-rich foods such as berries, green tea, onions, and broccoli into daily dietary habits, individuals can potentially boost their immune systems and reduce the risk of bacterial infections. Additionally, supplementing with polyphenol extracts in concentrated forms can provide a convenient and targeted way to ensure adequate intake of these beneficial compounds, potentially enhancing the body’s resilience against AMR-related challenges.
The synergistic effects of polyphenols with traditional antibiotics and their ability to combat biofilm formation further underscore their potential in supporting overall health and mitigating the impact of antimicrobial resistance on public well-being.
Current Research and Development:
1. Studies and Clinical Trials:** Ongoing research is exploring the antimicrobial potential of various polyphenols, including their mechanisms of action, effectiveness against resistant bacteria, and safety profiles.
2. Formulation Development:** Researchers are working on developing formulations and delivery methods to enhance the bioavailability and targeted delivery of polyphenols for optimal therapeutic outcomes.
3. Identification of Active Compounds:** Identifying specific polyphenols with the most potent antimicrobial properties and understanding their modes of action are key areas of focus for future research.
Some Challenges and Considerations:
1. Standardization and Quality Control:** Ensuring consistent polyphenol content and quality in products for antimicrobial use is essential for efficacy and safety.
2. Regulatory Approvals:** Meeting regulatory standards and demonstrating the safety and efficacy of polyphenol-based treatments are crucial steps in their broader adoption for addressing AMR.
3. Resistance Development:** Monitoring the potential for bacteria to develop resistance to polyphenols is essential to avoid the emergence of new antimicrobial resistance challenges.
Polyphenolic Disinfectants
As an incidental discovery, besides contributing to antibiotic-assisted treatment against antimicrobial resistance, polyphenols are great disinfectants – Polyphenolic Disinfectants.
The eco-friendly advantage of polyphenolic disinfectants, mean they are currently used not just in healthcare facilities around the world, but also in some domestic cleaners, where polyphenols such as thymol (isolated from thyme), carvacrol (extracted from oregano) and eugenol (obtained from clove) are integrated to both maintain hygiene at home, as well as help prevent the spread of infectious diseases in hospitals and health care facilities.
Conclusion:
The future of polyphenols in combating Antimicrobial Resistance looks really promising.
With expanding research efforts, potential synergies with existing treatments, and a focus on their role in both treatment and prevention, continuing exploration and development in this field holds significant promise for addressing the challenges posed by antimicrobial resistance and enhancing global health outcomes.