Herbs and Antimicrobial Resistance

by Guido Masé September 18, 2017

Antimicrobial resistance has followed on the heels of drug development since the very beginning – in fact, since before penicillin was ever released to the general public.1 Factors such as antibiotic overuse on humans and animals, incomplete medication cycles, and greater ease of pathogen concentration and transmission in our crowded, global lives have accelerated the evolution of microbial resistance. In the last decade, there has been an effort to slow it down, by pointing out needless medical prescribing patterns,2 layering or combining antibiotics to improve their lethality,3 and segregating the use of next-generation antibiotics as a “last resort.”4 Nevertheless, global spread of staph, malaria, and tuberculosis strains that are, in some cases, resistant to almost every pharmaceutical antimicrobial continues. Beyond this, global transmission of viral infections presents a difficult challenge as well.

The WHO and countries around the world are establishing guidelines for antibiotic use, and research to develop new drugs continues.5 But we may have to stop thinking of antibiotics as invincible weapons in a microbial war, and more like pieces of the co-evolutionary relationship we have with microbes: powerful in the right context, used in moderation, and never by themselves. So as we explore novel approaches, it can be useful to consider botanical antimicrobials, too: not as stand-alone agents, but as targeted synergists in the modern medical context.  

ElderberryBotanicals do contain strong antimicrobial compounds and, in many cases, these compounds can reach the systemic circulation in concentrations that are high enough to inhibit microbial growth. Often, these compounds exist as a few different variants inside one plant: built-in layering can help control resistance.6 Sometimes, we see a direct antimicrobial effect: artemisinin from sweet Annie enters the plasmodium and, by binding with heme, initiates a cascade of free radicals that ultimately oxidizes the parasite.7 There are many more antimicrobial mechanisms in the plant world, and they hold a lot of promise.

But an area almost completely neglected by modern tech medicine is the enhancement of host defense. This may be a consequence of the martial, battle-like cultural mentality around “fighting” infection: we see our weapons, and we see the enemy’s, but no one is paying attention to the field of battle. Think of an infection as a disruption in an ecosystem: beneficial and pathogenic organisms, the internal environment, and the surrounding ecology all play a role.

In this milieu, medicinal plants can alter the balance by slowing down pathogens, or by improving the resilience and efficiency of the ecosystem. We have been heavily invested in the first direction, and less so in the second (this may be changing, as we see in a recent review).8 But it is building resilience that should be a top priority when administering any antimicrobial prescription: for a more rapid return to baseline, and for a lower chance of developing resistance.

Some examples of plants being considered as novel antimicrobials

Potential botanical antimicrobials possess a broad spectrum of chemistry: either polyphenols, or volatile terpenes, or lactones like those found in Andrographis or Artemisia (two very bitter plants). Polyphenolic compounds in general show good activity if relatively high concentrations are achieved;9 this can be accomplished by consuming lots of those plants, or by purchasing a concentrated extract.

 

EGCG (epi-gallo-catechin-gallate), a flavonoid-family polyphenol from green tea leaves, is a promising candidate. It has the ability to synergize with conventional antibiotics, helping to prevent resistance,10 The sea buckthorn (Hippophae) shows similar effects,11 perhaps because of similar chemistry: it is rich in ellagitannins. Other botanicals are receiving attention for their ability to inhibit viral replication and spread, even in their whole form and as part of traditional herbal formulae.

 

Among these we find honeysuckle and forsythia flowers, but also the seeds of burdock–often combined in the Chinese herbal formula Yinqiaosan,12 recommended for “heat” conditions. Research pointing to the applicability of elderberry in similar conditions has been building over the last twenty years.13 For more antibacterial activity, preliminary research is identifying herbs that can affect multi-drug-resistant strains: Andrographis14 and Lantana camara,15 both originally native to the Indian subcontinent, seem able to inhibit bacterial growth even at low concentrations (especially for drug-resistant tuberculosis). Lantana is useful topically as well as internally.16

 

Lantana camaraSweet Annie, Artemisia annua, is the source of the antimalarial drug artemisinin,17 but it is also effective (and much less expensive) as an infusion or whole-plant remedy;18 given how easy it is to grow, and that it shows the same multi-constituent “layering” ability of most botanical antimicrobials,19 it is worth considering a whole-plant approach to malaria treatment to avoid compromising one of the only remaining effective antimalarial drugs.20 Bloodroot, Sanguinaria canadensis, is a member of the poppy family and related to the greater celandine (Chelidonium). It shares some of the same alkaloids with its cousin: chelerythrine, but also sanguinarine, are intense, caustic substances that have received a lot of attention for their ability to affect bacterial cell membranes21 and to inhibit the enzymes microbes need to read and copy DNA and RNA during reproduction.22 Finally, Baikal skullcap (S. baicalensis) has also show the ability to disrupt the internal signaling and DNA-processing ability of drug-resistant microbes like staph. This fits in with the traditional use pattern of Baikal skullcap for abscesses, skin infection, and overall “heat” symptoms – but we have yet to see pronounced clinical antimicrobial activity from this plant, with the exception of relatively topical applications (like gingivitis).24 This may be related to the type of chemistry we find in Baikal skullcap roots: polyphenols such as baicalin, again of the flavonoid family, are active when present at high concentrations, but these concentrations are difficult to achieve across the entire physiology due to bioavailability and distribution issues. 


Bloodroot
This brings up an important consideration: often, when exploring the botanical world for potential novel antimicrobials, we apply extracts to pathogens directly, and at high concentrations. This can be unrealistic in the real-world setting of the clinic: sometimes we can’t isolate and access the area of infection, or the pathogen has spread across the whole system. The results we’re seeing for medicinal plants are preliminary and, while hopeful, still need more exploration before we can recommend them confidently for clinical use as antibacterial agents. Fortunately, we have seen more systemic effects from herbs like Baikal skullcap when talking about the other part of our dance with the microbial world: they can optimize our host defenses.

Some examples of botanicals that enhance host defense

While some herbs are very effective in a petri dish, but disappoint at fighting infection in living organisms, the opposite is true of immune-tonic herbs: they have very little activity in petri dishes, but get them into a living being, and they help ensure that the immune response to pathogens is at its best (which often means more effective handling of infections). Think of Astragalus for immune health: it is a sweet root, and a decoction will start getting moldy and creating bacterial biofilms in less than 48 hours at room temperature. Nevertheless, it consistently shows the ability to balance and support optimal immune function.25 In this sense, it is inaccurate to say that Astragalus has antimicrobial activity: certainly, when taken orally, this seems to be its effect.

 

But it is the immune system that has the antimicrobial activity, and it is simply brought into optimal, efficient function by Astragalus (which is why the root has limited activity in a petri dish). The macrophages, neutrophils, T and B cells do the rest. How essential, then, to add some of these herbs into treatment protocols that involve antibiotics: more effective immune responses will translate to better pathogen clearance and less chances to develop resistance, while at the same time sparing the use of multiple antibiotics.

 


AstragalusWhile we see elderberry (and elderflower) studied for its ability to help with viral infections (and the polyphenol content does show antiviral effects in petri dishes),26 it may be the polysaccharide content of this plant that, by optimizing host defense, is most connected to the clinical effects of elder.27 Polysaccharides appear to be immune-active compounds, and they are found in other plants (from Astragalus to Echinacea) with clinically-relevant immunologic effects.28 Additionally, many mushrooms are rich in polysaccharides and seem useful in a range of pathologies: not because they fight cancer, or infection, or autoimmune disease, but because they support optimal host defenses, allowing the physiology to take the steps it needs to maintain health and balance.29

 

This is a critical point: by supporting the living system, we can often handle what challenges come our way. Clearly, this is not always the case, and this is why we have antimicrobial drugs. But even when taking these drugs, it is important to mind host defense if we are trying to decrease the spread of drug resistance.

 


ReishiOther phytochemicals know to support optimal host defenses are the saponins. These compounds are somewhat effective in petri dishes, but in living beings they act similarly to polysaccharides by ensuring that innate immunity is ready and vigilant, and that adaptive immunity is engaged and well-balanced.30 Bupleurum, a plant from the parsley family used in traditional Chinese medicine, contains compounds called saikosaponins that ensure effective T-cell responses.31 Finally the glycoalkaloids found in the nightshade family of plants – from potato leaves, to bittersweet nightshade leaves and berries – have received a lot of attention lately. While toxic in high quantities, when they are consumed at lower doses they seem able to ensure a vital, responsive host defense system.32 We have used bittersweet nightshade (Solanum dulcamara) to support immunity when folks are dealing with ongoing eruptive skin complaints; perhaps the immunologic activity of this plant is a helpful synergist in these cases. Glycoalkaloids don’t seem helpful at the onset of infection or in petri dishes; rather, they seem to be best at tonification over time – an effect consistent with the optimization of host defense.

Conclusion

As distressing as this admission might be, we seem unable to win a direct war against microbes. Their ability to rapidly evolve defense mechanisms and share information, as well as travel rapidly around the world as part of our global culture, makes the dream of eradicating infection an impossibility. Additionally, we are learning that not all microbes are enemies: in fact, pathogens are a very small fraction of the microbial world.33 In attempting to develop reliable medical technology for handling virulent infections, it is time for us to start building systems characterized by fewer antibiotics used and dispersed into the environment; the combination of legacy drugs and novel botanical antimicrobial cocktails that lessen the chance for resistance to develop; and a focused attention on the optimization of host defense to ensure greater resilience and fewer infections to begin with. But to do this, we must shift away from the antimicrobial war, and towards a wellness ecology that values tonification, nurturing, and diversity: not only within each person, but in our communities, lawns, gardens, forests and fields. An ecology that is truly well supports organisms that are less prone to disruption from pathogens. And, when disruption does occur, we will have powerful and effective drugs that still work, along with the wisdom to use them well.  

 

Guido Masé is a clinical herbalist, herbal educator, and garden steward specializing in holistic Western herbalism, though his approach is eclectic and draws upon many influences. Guido works clinically and teaches at the Vermont Center for Integrative Herbalism and is a professional member of the American Herbalists Guild. He is the author of The Wild Medicine Solution: Healing with Aromatic, Bitter and Tonic Plants.

 

Footnotes

  1. https://www.cdc.gov/drugresistance/about.html
  2. Malhotra-Kumar, Surbhi, et al. “Effect of azithromycin and clarithromycin therapy on pharyngeal carriage of macrolide-resistant streptococci in healthy volunteers: a randomised, double-blind, placebo-controlled study.” The Lancet 369.9560 (2007): 482-490.
  3. Torella JP, Chait R, Kishony R. Optimal Drug Synergy in Antimicrobial Treatments. PLoS Computational Biology, 6(6), e1000796 (2010).
  4. Resolution WHA68.7 of the SIXTY-EIGHTH WORLD HEALTH ASSEMBLY. Global action plan on antimicrobial resistance. Available at: http://apps.who.int/gb/ebwha/pdf_files/WHA68/A68_R7-en.pdf
  5. Inoue H. Antimicrobial resistance: translating political commitment into national action. Bulletin of the World Health Organization, 95(4), 242-242 (2017).
  6. Wallaart, T. Eelco, et al. “Seasonal variation of artemisinin and its biosynthetic precursors in plants of Artemisia annua of different geographical origin: proof for the existence of chemotypes.” Planta Medica 66.01 (2000): 57-62./note] In other cases, plants interfere with the ability of viruses to gain entry into our cells by sabotaging enzymes such as neuraminidase.[note]Liu, Ai-Lin, et al. “Structure–activity relationship of flavonoids as influenza virus neuraminidase inhibitors and their in vitro anti-viral activities.” Bioorganic & medicinal chemistry 16.15 (2008): 7141-7147.
  7. O’neill, Paul M., Victoria E. Barton, and Stephen A. Ward. “The molecular mechanism of action of artemisinin—the debate continues.” Molecules 15.3 (2010): 1705-1721.
  8. Enioutina, Elena Yu, et al. “Phytotherapy as an alternative to conventional antimicrobials: Combating microbial resistance.” Expert Review of Clinical Pharmacology just-accepted (2017).
  9. Daglia, Maria. “Polyphenols as antimicrobial agents.” Current opinion in biotechnology 23.2 (2012): 174-181.
  10. Zhao WH, Hu ZQ, Okubo S, Hara Y, Shimamura T. Mechanism of synergy between epigallocatechin gallate and beta-lactams against methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother, 45(6), 1737-1742 (2001)./note] and also has appreciable antiviral activity on its own.[note]Steinmann, J., et al. “Anti‐infective properties of epigallocatechin‐3‐gallate (EGCG), a component of green tea.” British journal of pharmacology 168.5 (2013): 1059-1073.
  11. Sheichenko OP, Sheichenko ON, Tolkachev ON et al. Comprehensive Study of Antiviral Polyphenols of Seabuckthorn Leaves/Seabuckthorn (Hippophae L.): A Мultipurpose Wonder Plant. In: Emerging Trend in Research Technologies Singh, V (Ed. (Daya Publishing House, New Delhi, 2014) 383-392.
  12. Wang C, Cao B, Liu Q, et al. Oseltamivir compared with the chinese traditional therapy maxingshigan–yinqiaosan in the treatment of h1n1 influenza: A randomized trial. Annals of Internal Medicine, 155(4), 217-225 (2011).
  13. Kinoshita, Emiko, et al. “Anti-influenza virus effects of elderberry juice and its fractions.” Bioscience, biotechnology, and biochemistry 76.9 (2012): 1633-1638. Zakay-Rones, Z., et al. “Randomized study of the efficacy and safety of oral elderberry extract in the treatment of influenza A and B virus infections.” Journal of International Medical Research 32.2 (2004): 132-140. Zakay-Rones, Zichria, et al. “Inhibition of several strains of influenza virus in vitro and reduction of symptoms by an elderberry extract (Sambucus nigra L.) during an outbreak of influenza B Panama.” The Journal of Alternative and Complementary Medicine 1.4 (1995): 361-369.
  14. Radji, Maksum, Marita Kurniati, and Ariyani Kiranasari. “Comparative antimycobacterial activity of some Indonesian medicinal plants against multi-drug resistant Mycobacterium tuberculosis.” (2015).
  15. Kirimuhuzya, Claude, et al. “The anti-mycobacterial activity of Lantana camara a plant traditionally used to treat symptoms of tuberculosis in South-western Uganda.” African health sciences 9.1 (2009): 40-45.
  16. Pattnaik, Smaranika, and Banita Pattnaik. “A study of Lantana camara linn aromatic oil as an antibacterial agent.” Intr. J. pharm. sci 1.1 (2010): 32-35.
  17. Tu, Youyou. “The discovery of artemisinin (qinghaosu) and gifts from Chinese medicine.” Nature medicine 17.10 (2011): 1217-1220.
  18. Elfawal, Mostafa A., et al. “Dried whole plant Artemisia annua as an antimalarial therapy.” PLoS One 7.12 (2012): e52746.
  19. Rasoanaivo, Philippe, et al. “Whole plant extracts versus single compounds for the treatment of malaria: synergy and positive interactions.” Malaria Journal 10.1 (2011): S4.
  20. Ogwang, Patrick E., et al. “Use of Artemisia annua L. Infusion for Malaria Prevention: Mode of Action and Benefits in a Ugandan Community.” (2011).
  21. Miao, Fang, et al. “Structural modification of sanguinarine and chelerythrine and their antibacterial activity.” Natural product research 25.9 (2011): 863-875.
  22. Vichkanova S, Fateeva T, Krutikova N et al. Sanguiritrin. Gift of nature to humans. [in Russian] (OneBook.ru, Moscow, Russia, 2015
  23. Shi G, Shao Q, Wang T, Wang C. New advance in studies on antimicrobial activity of Scutellaria baicalensis and its effective ingredients. China Journal of Chinese Materia Medica 39(19), 3713-3718 (2014).
  24. Arweiler, Nicole Birgit, et al. “Clinical and antibacterial effect of an anti-inflammatory toothpaste formulation with Scutellaria baicalensis extract on experimental gingivitis.” Clinical oral investigations 15.6 (2011): 909-913.
  25. Cho, William Chi Shing, and Kwok Nam Leung. “In vitro and in vivo immunomodulating and immunorestorative effects of Astragalus membranaceus.” Journal of ethnopharmacology 113.1 (2007): 132-141.
  26. Mohammadsadeghi, Shahin, et al. “The antimicrobial activity of elderberry (Sambucus nigra L.) extract against gram positive bacteria, gram negative bacteria and yeast.” Res J App Sci 8.4 (2013): 240-3.
  27. Hilde, Barsett, et al. “Comparison of Carbohydrate Structures and Immunomodulating Properties of Extracts from Berries and Flowers of Sambucus nigra L.” (2012).
  28. Ferreira, Sónia S., et al. “Structure–function relationships of immunostimulatory polysaccharides: A review.” Carbohydrate polymers 132 (2015): 378-396.
  29. Wasser, S. P. “Medicinal mushrooms as a source of antitumor and immunomodulating polysaccharides.” Applied microbiology and biotechnology 60.3 (2002): 258-274.
  30. Francis, George, et al. “The biological action of saponins in animal systems: a review.” British journal of Nutrition 88.6 (2002): 587-605.
  31. Patel K. A review on herbal immunoadjuvant. Int. J. of Pharm. & Life Sci. (IJPLS), 3(3), 1568-1576 (2012).
  32. Gubarev MI, Enioutina EY, Taylor JL, Visic DM, Daynes RA. Plant-derived glycoalkaloids protect mice against lethal infection with Salmonella typhimurium.
  33. *About 1,500 species are pathogenic, out of millions. Taylor, Louise H., Sophia M. Latham, and E. J. Mark. “Risk factors for human disease emergence.” Philosophical Transactions of the Royal Society of London B: Biological Sciences 356.1411 (2001): 983-989.
Guido Masé
Guido Masé


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