A Cell Wall for Us All

By Patric Soce

            The study of medicine arguably has been around for hundreds if not thousands of years. With so much time available, one can only think about all the advancements and remarkable discoveries made. For example, the discovery of penicillin, first discovered by Dr. Alexander Fleming in 1928 which officially started saving lives by 1942. Such a great development can only be humbled by a massive response from microorganisms increasing their bacterial resistance. The history of penicillin is a great example demonstrating the life saving capabilities of new drugs but also the underlying danger created. In his acceptance speech for the Noble Prize in medicine, Fleming warned of the emergence of bacterial resistance. Almost a century later, we now find ourselves in an “arms race” against disease causing agents often including viral, bacterial, and organismal sources. So where do we look for new treatments or therapies when applying this to parasitism?

            Often, it is easy to overlook areas of our lives and in research, I believe we have done so with the study of medicine. A severely underrepresented field in parasitology are plant immune capabilities and their application to medical practices. Consider a current cause of death for over 700,000 people today, most of which are children under five years old! The culprit, Plasmodium falciparum the parasite responsible for malaria. Virtually all cures available for malaria currently can be traced back to plant origin such as Artemisinin a terpene made by the plant Artemisia. Or quinoline alkaloids from Chinchoa bark used to make semisynthetic chloroquine to treat the bloodworm stage of Plasmodium. Surprisingly over 1,200 plants have been shown to carry antimalarial properties but because a lack of clinical trials exist, we have little to show. A term often used to describe the antiparasitic or useful substances in plants are ‘secondary metabolites’ which are non-essential to growth but useful in plant preservation.

            The plant Artemisia annua, also known as Wormwood, has an extensive medical history in our species dating back 2000 years ago in ancient china. Today it is not only used to treat malaria but also African sleeping sickness, and Chagas’ disease, both are caused by trypanosomes or blood parasites. Interestingly, wormwood extract has been shown to target and kill cancer cells within a host and is also used in the treatment of Onchocerciasis (river blindness). The secondary metabolite responsible for treatment of malaria and trypanosome infection is Artemisinin, but this is also a false statement. It is known that secondary metabolites in plants can have synergistic interactions, meaning that once two or more substances are combined, they can have a sum effect greater than their initial capability. Such is the result when a secondary metabolite of green tea (EGCG), is combined with digitonin of the Foxglove plant resulting in a severely lowered mortality rate and survival of P. berghei (malaria). The idea of synergistic interactions is often understudied and seems to be an emerging practice in the immunoparasitology field, but such is the case with developing any new medicines.

            It should be known that Artemisia is only one of many plants used and studied when measuring anti-parasitic properties. The two most well-known parasitic infections in the world include Malaria and Trypanosomiasis, they also have the largest degree of research in response to secondary metabolites. In a 2015 study by AL-Ani et al. When the bee venom melittin is combined with secondary metabolites such as carvacrol (from cilantro) a synergistic interaction is observed inhibiting microbe infection. Although this example only deals in response to bacteria, we see potential and it makes us excited. Like with developing any new medicine, a target must be chosen and although parasites are eukaryotic creatures like us, they have no deficit in this area. Possible targets of parasites include DNA/RNA, supporting structures of the cell (cytoskeleton), and the bio-membranes (cuticle) of parasites.

            When targeting the DNA or RNA of a parasitic infection, two methods are available to us by secondary metabolites, alkylation, and intercalating. Alkylation is the process of molecules forming double bonds with individual DNA bases, this double bond then inhibits the process of DNA replication causing death. A secondary metabolite that does such, originates from the Birthwort flower and is a known carcinogen called Aristolochic acid. Just as with wormwood, birthwort flower has an extensive history being a traditional medicine whose usefulness correlates with concentration. An Intercalating molecule like Berberine from the Barbary bush most often causes mutations in DNA replication (frameshift/deletion) resulting in death (of the parasite). This is achieved by insertion of the molecule between complementary base pairs further stabilizing the double helix. And when targeting cellular proteins or structures, we need to pick key moments in the cell cycle typically during division. Colchicine, a substance produced by the flower species Colchicum has an affinity for microtubules and can prevent formation by adhering to tubulin, leading to the prevention of cell division. Other methods like this target key steps in division and ironic enough, can stop division by preventing the degradation of the microtubules. Because parasites often do not have lungs or gills, they must exchange gas through their skin, and knowing this we have found our next target, the bio-membrane. In order to harm the membrane, we only need to disturb it enough to affect the level of permeability used to contain and prevent certain molecules entering the parasite. And you bet there is a secondary metabolite capable of this, usually involving terpenes and phenylpropanoids!

            As most of us probably learned as children; if you play with fire, you are going to get burned. In this case, we are not necessarily playing with fire, but taking and altering naturally produced molecules (most of which are toxic) for our own uses. Just as eukaryotic plant cells utilize a cell wall, perhaps we can integrate a cell wall into ourselves (metaphorically). This “cell wall” for us would most likely contain a variety of secondary metabolites utilizing their unique synergetic interactions to cure any disease, especially the parasitic! Hopefully now we understand how many different methods are available when combating parasites and the importance of naturally occurring molecules available. But the problem is presented as we are still in the human “arms race” against disease, a war technically against nature.

References

Current Status of Malaria. (2011, September 24). MALARIA.COM | Malaria Information, Research and News. https://www.malaria.com/questions/malaria-current-status

Editors of Encyclopaedia Britannica. (1998, July 20). Aristolochiaceae. Encyclopedia Britannica. https://www.britannica.com/plant/Aristolochiaceae

Issam, A. A., Zimmermann, S., Reichling, J., & Wink, M. (2015). Pharmacological synergism of bee venom and melittin with antibiotics and plant secondary metabolites against multi-drug resistant microbial pathogens. Phytomedicine, 22(2), 245-255.

Markel, H. (2013, September 27). The real story behind penicillin. PBS NewsHour. https://www.pbs.org/newshour/health/the-real-story-behind-the-worlds-first-antibiotic

National Cancer Institute. (2019, January 14). Aristolochic acids - cancer-causing substances. https://www.cancer.gov/about-cancer/causes-prevention/risk/substances/aristolochic-acids

Nootriment. (2019, December 20). Artemisinin effects, health benefits and uses. World Health Source, LLC. https://worldhealthsource.com/artemisinin-effects-health-benefits-and-uses/

Phillips R. S. (2001). Current status of malaria and potential for control. Clinical microbiology reviews, 14(1), 208–226. https://doi.org/10.1128/CMR.14.1.208-226.2001

Wink, M. (2012). Medicinal plants: a source of anti-parasitic secondary metabolites. Molecules, 17(11), 12771-12791.