Botanical Therapy for Antibiotic Resistance in the GI Tract

Antibiotic resistance (AR) is a global public health crisis with far-reaching consequences. With the spread of AR, previously treatable infections have become challenging, and often impossible, to treat. According to the Center for Disease Control's recently released 2019 AR Threat Report, each year in the United States there are more than 2.8 million AR infections, resulting in 35,000 deaths. Even though these numbers have decreased by approximately 18% since 2013, the numbers are unacceptably high.

Antibiotic resistance (AR) is a global public health crisis with far-reaching consequences. With the spread of AR, previously treatable infections have become challenging, and often impossible, to treat. According to the Center for Disease Control's recently released 2019 AR Threat Report, each year in the United States there are more than 2.8 million AR infections, resulting in 35,000 deaths. Even though these numbers have decreased by approximately 18% since 2013, the numbers are unacceptably high.

Antibiotics are life-saving medications when used in the correct context. Any time antibiotics are used, a strain of bacteria can develop resistance. Since the resistant bacteria aren't killed by the antibiotic, they will continue colonizing. Continued use of the same antibiotic will select for resistant strains and may reduce numbers of protective bacterial strains. Bacteria are incredibly clever and are able to rapidly share resistance genes within and between species, leading to resistance in bacteria that have never encountered an antibiotic.

Developing novel antibiotics is a huge undertaking and, while pharmaceutical companies are working on new classes of antibiotics, it is clear we are not equipped to keep pace with the rapidly adapting microbial world.

Mechanisms of Antibiotic Resistance

Antibiotic resistance occurs when microorganisms develop the ability to overcome the antibiotics designed to kill them. Bacteria have numerous strategies to resist antibiotics. Gram-negative organisms tend to display more AR strategies than do gram positive organisms. This is mostly due to the presence of a double cell membrane. The periplasmic space between the two membranes of gram-negative organisms acts as a protective holding chamber, giving the bacteria a chance to react before the antibiotics can access the inside of the cell.

Testing for AR genes can help to characterize resistant infections and can aid in selecting effective therapies. Some of the key AR strategies are detailed below.

Preventing Access of Antibiotics to the Inside of the Cell

Altered uptake – Organisms are able to alter the permeability of their cell membrane, making it more difficult for antibiotics to enter the cell.

Efflux pumps – Trans-membrane pumps that are able recognize antibiotics and other substances and rapidly pump them out of the cell. Both gram positive and gram-negative organisms are able to use efflux pumps. In gram positive organisms, efflux pumps must work much more rapidly to protect the cells from antibiotic damage, because they do not have a protective double membrane.

Target Modification

Each antibiotic class has a specific target within a microorganism (nucleus, DNA, RNA, proteins, cell wall etc.). Mutations can alter the structure of the target so that the antibiotics can no longer bind to and act on the target. Microorganisms can also protect antibiotic targets and/or make them obsolete to cell function.

Enzymatic Degradation

Enzymes are proteins that are able to break down antibiotics. The most notable enzymes are β-lactamases, which are used to break down the β-lactam (penicillin) family of antibiotics.

Quorum Sensing

When the population of bacteria reaches a critical level, they release signaling molecules into their environment. These molecules, known as auto-inducers, can precipitate a number of different effects including biofilm formation, gene transfer, virulence or toxin production.

The Use of Botanicals Against Antibiotic Resistant Bacteria

The world of botanical medicine offers promising potential in the fight against AR bacteria. Herbs have been used traditionally to treat infections for hundreds of years. While many herbs are used empirically against bacterial infection, others have extensive research on the individual constituents and actions against bacteria.

When it comes to treating antibiotic resistance in the GI tract, there are two main strategies that can be used;

• choosing botanicals for their direct antimicrobial effects AND
• choosing botanicals as synergists to directly target AR mechanisms.

Below are listed some key antimicrobial botanicals and their mechanisms of action.

Botanicals as Antimicrobial Agents

There are many herbs that have evidence of antimicrobial activity, both locally and systemically. The following is a short list of herbs that are especially effective as local antimicrobials. When it comes to multi-drug resistant bacteria, combining multiple whole-herb extracts is a beneficial strategy.

Berberine-containing herbs – Mahonia aquifolium, Hydrastis canadensis, Coptis chinensis etc.

Berberine herbs are very effective antimicrobials. Standardized berberine extracts are readily available. However, research indicates that whole-herb extracts have stronger antimicrobial activity than standardized berberine.

Wormwood – Artemisia absinthium

Artemisia is a very effective antimicrobial with a long history of traditional use against bacteria, fungi and parasites.

Garlic – Allium sativum

Allium has proven effectiveness as an antimicrobial. Greater effects are seen with fresh crushed garlic than with water extraction.

Old Man's Beard – Usnea barbata

Usnea and other lichens have very strong antimicrobial effects against both gram positive and gram negative bacteria, especially when used as a strong ethanol extract.

Clove – Syzygium spp.

Syzygium is effective against numerous gram negative and gram-positive bacteria as both ethanol and water extraction.

Botanicals as Targeted Synergists in Combination Therapy

The following botanicals can be used in strategic combination with antibiotics or antimicrobial herbs. The following herbs have been shown to have specific action against AR mechanisms. The use of synergists can decrease the amount of antibiotic needed to be effective against bacteria. Synergists can also be used as adjuncts to herbal antimicrobial therapy. Note that some species of herb fall under more than one category. This is because each plant contains hundreds of individual constituents, which may have varied activity against bacteria and the microbial world.

• Efflux Pump Inhibitors
  • Licorice – Glycyrrhiza glabra
  • Milk Thistle – Silybum marianum
  • Green tea – Camellia sinensis
  • Sweet flag – Acorus calamus
  • Wormwood – Artemesia absinthium
  • Chinese skullcap – Scutellaria baicalensis

• β-Lactamase Inhibitors
  • Chinese skullcap – Scutellaria baicalensis
  • Green tea – Camellia sinensis

• Quorum Sensing Inhibitors
  • Green tea – Camellia sinensis
  • Sweet flag – Acorus calamus
  • Rosemary – rosmarinus officinale

Putting it Together

While antibiotic therapy is a necessary and very effective solution for most bacterial infections, they have proven to be insufficient against AR strains. Botanical therapy offers promising solutions to combat multi-drug resistant bacteria. Bactericidal herbs can be used either instead of or in addition to antibiotic therapy. In addition to this, whole herb extracts can be used synergistically to make antibiotic or herbal antimicrobial therapy more effective. Testing for AR genes can help to guide treatment. Antibiotics and botanicals can be selected strategically based on known and suspected AR mechanisms.

References:

1. Abdallah, E. M., & Abdallah, E. M. (2016). Medicinal plants as an alternative drug against methicillin resistant Staphylococcus aureus. Int J Microbiol Allied Sci, 3(1), 35-42.
2. Blair, J. M., Webber, M. A., Baylay, A. J., Ogbolu, D. O., & Piddock, L. J. (2015). Molecular mechanisms of antibiotic resistance. Nature reviews microbiology, 13(1), 42-51.
3. Cansaran, D., Kahya, D., Yurdakulol, E., & Atakol, O. (2006). Identification and quantitation of usnic acid from the lichen Usnea species of Anatolia and antimicrobial activity. Zeitschrift f&uumi;r Naturforschung C, 61(11-12), 773-776.
4. CDC. Antibiotic Resistance Threats in the United States, 2019. Atlanta, GA: U.S. Department of Health and Human Services, CDC; 2019.
5. Cech, N. B., Junio, H. A., Ackermann, L. W., Kavanaugh, J. S., & Horswill, A. R. (2012). Quorum quenching and antimicrobial activity of goldenseal (Hydrastis canadensis) against methicillin-resistant Staphylococcus aureus (MRSA). Planta medica, 78(14), 1556-1561.
6. Chanda, S., & Rakholiya, K. (2011). Combination therapy: Synergism between natural plant extracts and antibiotics against infectious diseases. Microbiol Book Series, 520-529.
7. Chopra, I., Hodgson, J., Metcalf, B., & Poste, G. (1997). The search for antimicrobial agents effective against bacteria resistant to multiple antibiotics. Antimicrobial agents and chemotherapy, 41(3), 497.
8. de Breij, A., Karnaoukh, T. G., Schrumpf, J., Hiemstra, P. S., Nibbering, P. H., van Dissel, J. T., & de Visser, P. C. (2016). The licorice pentacyclic triterpenoid component 18β-glycyrrhetinic acid enhances the activity of antibiotics against strains of methicillin-resistant Staphylococcus aureus. European Journal of Clinical Microbiology & Infectious Diseases, 35(4), 555-562.
9. Djipa, C. D., Delmée, M., & Quetin-Leclercq, J. (2000). Antimicrobial activity of bark extracts of Syzygium jambos (L.) Alston (Myrtaceae). Journal of Ethnopharmacology, 71(1-2), 307-313.
10. Dreier, J., & Ruggerone, P. (2015). Interaction of antibacterial compounds with RND efflux pumps in Pseudomonas aeruginosa. Frontiers in microbiology, 6, 660.
11. Ettefagh, K. A., Burns, J. T., Junio, H. A., Kaatz, G. W., & Cech, N. B. (2011). Goldenseal (Hydrastis canadensis L.) extracts synergistically enhance the antibacterial activity of berberine via efflux pump inhibition. Planta medica, 77(08), 835-840.
12. Fiamegos, Y. C., Kastritis, P. L., Exarchou, V., Han, H., Bonvin, A. M., Vervoort, J., ... & Tegos, G. P. (2011). Antimicrobial and efflux pump inhibitory activity of caffeoylquinic acids from Artemisia absinthium against gram-positive pathogenic bacteria. PLoS One, 6(4), e18127.
13. Giedraitienė, A., Vitkauskienė, A., Naginienė, R., & Pavilonis, A. (2011). Antibiotic resistance mechanisms of clinically important bacteria. Medicina, 47(3), 19.
14. Gupta, P. D., & Birdi, T. J. (2017). Development of botanicals to combat antibiotic resistance. Journal of Ayurveda and integrative medicine, 8(4), 266-275.
15. Iwalokun, B. A., Ogunledun, A., Ogbolu, D. O., Bamiro, S. B., & Jimi-Omojola, J. (2004). In vitro antimicrobial properties of aqueous garlic extract against multidrug-resistant bacteria and Candida species from Nigeria. Journal of medicinal food, 7(3), 327-333.
16. Jabar, M. A., & Al-Mossawi, A. (2007). Susceptibility of some multiple resistant bacteria to garlic extract. African Journal of Biotechnology, 6(6).
17. Karuppiah, P., & Rajaram, S. (2012). Antibacterial effect of Allium sativum cloves and Zingiber officinale rhizomes against multiple-drug resistant clinical pathogens. Asian Pacific journal of tropical biomedicine, 2(8), 597-601.
18. Koh, K. H., & Tham, F. Y. (2011). Screening of traditional Chinese medicinal plants for quorum-sensing inhibitors activity. Journal of Microbiology, Immunology and Infection, 44(2), 144-148.
19. Lallemand, B., Gelbcke, M., Dubois, J., Prévost, M., Jabin, I., & Kiss, R. (2011). Structure-activity relationship analyses of glycyrrhetinic acid derivatives as anticancer agents. Mini reviews in medicinal chemistry, 11(10), 881-887.
20. Lambert, P. A. (2002). Mechanisms of antibiotic resistance in Pseudomonas aeruginosa. Journal of the royal society of medicine, 95(Suppl 41), 22.
21. LIU, P., YE, H. F., CHEN, H. L., & LI, S. W. (2006). A study on the bacteriostatic action of 5 Chinese herbs against β-lactamases-producing bacteria [J]. Chinese Journal of Microecology, 1.
22. LIU, I. X., DURHAM, D. G., & RICHARDS, R. M. E. (2000). Baicalin synergy with β-lactam antibiotics against methicillin-resistant Staphylococcus aureus and other β-lactam-resistant strains of S. aureus. Journal of Pharmacy and Pharmacology, 52(3), 361-366.
23. Lopes-Lutz, D., Alviano, D. S., Alviano, C. S., & Kolodziejczyk, P. P. (2008). Screening of chemical composition, antimicrobial and antioxidant activities of Artemisia essential oils. Phytochemistry, 69(8), 1732-1738.
24. Madamombe, I. T., & Afolayan, A. J. (2003). Evaluation of antimicrobial activity of extracts from South African Usnea barbata. Pharmaceutical biology, 41(3), 199-202.
25. Moslemi, H. R., Hoseinzadeh, H., Badouei, M. A., Kafshdouzan, K., & Fard, R. M. N. (2012). Antimicrobial activity of Artemisia absinthium against surgical wounds infected by Staphylococcus aureus in a rat model. Indian journal of microbiology, 52(4), 601-604.
26. Musumeci, R., Speciale, A., Costanzo, R., Annino, A., Ragusa, S., Rapisarda, A., ... & Iauk, L. (2003). Berberis aetnensis C. Presl. extracts: antimicrobial properties and interaction with ciprofloxacin. International journal of antimicrobial agents, 22(1), 48-53.
27. Nazzaro, F., Fratianni, F., & Coppola, R. (2013). Quorum sensing and phytochemicals. International journal of molecular sciences, 14(6), 12607-12619.
28. Oliveira, G. F. D., Furtado, N. A. J. C., Silva Filho, A. A. D., Martins, C. H. G., Bastos, J. K., & Cunha, W. R. (2007). Antimicrobial activity of Syzygium cumini (Myrtaceae) leaves extract. Brazilian Journal of Microbiology, 38(2), 381-384.
29. Pundir, R. K., Jain, P., & Sharma, C. (2010). Antimicrobial activity of ethanolic extracts of Syzygium aromaticum and Allium sativum against food associated bacteria and fungi. Ethnobotanical Leaflets, 2010(3), 11.
30. Rhayour, K., Bouchikhi, T., Tantaoui-Elaraki, A., Sendide, K., & Remmal, A. (2003). The mechanism of bactericidal action of oregano and clove essential oils and of their phenolic major components on Escherichia coli and Bacillus subtilis. Journal of essential oil research, 15(5), 356-362.
31. Sáenz, Y., Brinas, L., Domínguez, E., Ruiz, J., Zarazaga, M., Vila, J., & Torres, C. (2004). Mechanisms of resistance in multiple-antibiotic-resistant Escherichia coli strains of human, animal, and food origins. Antimicrobial agents and chemotherapy, 48(10), 3996-4001.
32. Shaheen, A. Y., Sheikh, A. A., Rabbani, M., Aslam, A., Bibi, T., Liaqat, F., ... & Rehmani, S. F. (2015). Antibacterial activity of herbal extracts against multi-drug resistant Escherichia coli recovered from retail chicken meat. Pakistan journal of pharmaceutical sciences, 28(4).
33. Srivastava, P., Upreti, D. K., Dhole, T. N., Srivastava, A. K., & Nayak, M. T. (2013). Antimicrobial property of extracts of Indian lichen against human pathogenic bacteria. Interdisciplinary perspectives on infectious diseases, 2013.
34. Stapleton, P. D., Shah, S., Anderson, J. C., Hara, Y., Hamilton-Miller, J. M., & Taylor, P. W. (2004). Modulation of β-lactam resistance in Staphylococcus aureus by catechins and gallates. International journal of antimicrobial agents, 23(5), 462-467.
35. Stavri, M., Piddock, L. J., & Gibbons, S. (2006). Bacterial efflux pump inhibitors from natural sources. Journal of antimicrobial chemotherapy, 59(6), 1247-1260.
36. Stermitz, F. R., Beeson, T. D., Mueller, P. J., Hsiang, J. F., & Lewis, K. (2001). Staphylococcus aureus MDR efflux pump inhibitors from a Berberis and a Mahonia (sensu strictu) species. Biochemical systematics and ecology, 29(8), 793-798.
37. Stermitz, F. R., Tawara-Matsuda, J., Lorenz, P., Mueller, P., Zenewicz, L., & Lewis, K. (2000). 5 '-Methoxyhydnocarpin-D and Pheophorbide A: Berberis Species Components that Potentiate Berberine Growth Inhibition of Resistant Staphylococcus a ureus. Journal of natural products, 63(8), 1146-1149.
38. Stermitz, F. R., Lorenz, P., Tawara, J. N., Zenewicz, L. A., & Lewis, K. (2000). Synergy in a medicinal plant: antimicrobial action of berberine potentiated by 5′-methoxyhydnocarpin, a multidrug pump inhibitor. Proceedings of the National Academy of Sciences, 97(4), 1433-1437.
39. Tegos, G., Stermitz, F. R., Lomovskaya, O., & Lewis, K. (2002). Multidrug pump inhibitors uncover remarkable activity of plant antimicrobials. Antimicrobial agents and chemotherapy, 46(10), 3133-3141.
40. Thakur, P., Chawla, R., Goel, R., Arora, R., & Sharma, R. K. (2013). In silico modeling for Identification of promising antimicrobials of Herbal origin against highly virulent pathogenic strains of bacteria like New Delhi Metallo-beta-lactamase-1 Escherichia coli. Int. J. Innov. Appl. Stud, 4, 582-592.
41. Zhao, W. H., Hu, Z. Q., Okubo, S., Hara, Y., & Shimamura, T. (2001). Mechanism of synergy between epigallocatechin gallate and β-lactams against methicillin-resistant Staphylococcus aureus. Antimicrobial agents and chemotherapy, 45(6), 1737-1742.