Invasive Weed Species as a Source of Antimicrobials – Making the Best of a Bad Situation

Invasive Weed Species as a Source of Antimicrobials – Making the Best of a Bad Situation

Humans have always been dependant on nature to cater for their basic needs such a food and shelter but also for medicines. Initially medicines were in the form of crude treatments such as tinctures, teas, poultices, powders and other herbal formulations. The specific plants and methods of applications were originally passed down through oral history untill the information were recorded in herbals. In more recent history the use of natural products as medicines involves the isolation of active compounds [1]. The first active compound to be isolated in this way was morphine from opium by Friedrich Setürner in 1804 [2]. Drug discovery from plants also led to the isolation of many early drugs such as cocaine, codeine, digitoxin and quinine; some of which are still in use today. Due to the vast diversity of natural products ranging from teraestrial plants to marine organisms also incuding microorganisms and their infinite possible applications the isolation and characterisation for medicinal purposes continues today.
Plants have been the single most productive source of leads for the development of drugs, particularly as anti-cancer agents and anti-infectives [3]. Eventhough natural products have been a plentyful and continuous stream of useful drugs their use has dimished in the past two decade due to the major pharaceutical companies deminishing their interest in natural products. Due to slow nature of natural product discovery and its incompatiblity with high throughput screening (HTS) directed at moleculat targets [4]. Many large screening collections have been dissapointing in practice (these libraries containing a range of compounds from many different sources) natural products are the most diverse class of compounds with a significantly higher hit rate compared to fully synthetic and combinatorial libraries [5]. Furthermore, it has been shown that 83% of core ring scaffolds that are present in natural products are not present in commercially available screening libraries leading to fewer drug leads [6]. It is unsurprisingly that even with the introduction of new methods and technologies natural products have contributed massively to the drugs which have been approved in recent years (see Fig.1).

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Figure 1: Contributuion of Natural Products to Approved Drugs between 1981-2010; n=1355. (Adapted from Newman and Cragg 2012 [7])

My PhD funded by the Life Sciences Research Network Wales (http://www.lsrnw.ac.uk/). The project is based on the discovery of antimicrobal compounds form invasive weed species. Invasive non-native weed species are a significant global concern. These are resposible for a loss of biodiversity, altering ecological processes, impacting ecosystem services resulting in a cost of $35 billion annually in the USA [8-10]. If antimicrobial or any bioactive compounds could be sources from these problematic plants then we could at least draw one positive from their unwanted presence within our environment. This project includes the traditional extraction, isolation and characterisation of active compounds form plants followed by biological assays to test a range of biological activites of the compounds extracted. These techinques are also combined with the genomic and bioinformational approaches to aid and improve drug discovery. A wide range of plants were selected for this study and a range of compounds have been extracted from each with a range of interesting biological activites; especially antimicrobial activity. The most active plants tested were Japanese knotweed and Himalayan balsam.

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Resveratrol was found to be the most active antimicrobial compounds present in Japanese Knotweed. This compounds is also found in spermatophytes, such as grapevines and has been linked to a wide variety of biological activites. It has been reported to have antioxidant, anticancer, anti-inflammatory, prevent post-menopausal bone loss, and a range of positive metabolic effects. Resveratrol has also been suggested as the causal link between increased red wine consuption and decreased risk of heart disease [11].
A key compound has been found in Himalayan balsam which is by far the most potant antimicrobial compound in all the plants studied. It has a minimum inhibitor concentration of between 3-15 µg/mL agaisnt a range of Staphylococcal species. This compound has also been found to be non-toxic against mammlian cells. Similar compounds have also been show to have anti-cancer and anti-fungal activity.
The mode of action of these compounds are currently being elucidated using genomic, metabolomic and proteominc approaches combined with novel assays and cytometric techniques. In addition to this I aim to improve the activity of these compounds using computer aided drug design (CADD) through the Life Sciences Reseach Network Wales CADD Platform (http://www.lsrnw.ac.uk/platform-technologies/welsh-computer-aided-drug-design-cadd-platform/).
Natural products have been a source of drugs which have revolutionalised treatment of disease. It is clear that natural sources will contiune to play a significant role in the fight against disease and should be combined with new inovative methods which are currently being developed to form a multidisciplinary approach to treat disease.

References
1. Balunas, M.J. and A.D. Kinghorn, Drug discovery from medicinal plants. Life sciences, 2005. 78(5): p. 431-441.
2. Schmitz, R., Friedrich Wilhelm Sertürner and the discovery of morphine. Pharmacy in history, 1985. 27(2): p. 61-74.
3. Harvey, A.L., Natural products in drug discovery. Drug discovery today, 2008. 13(19): p. 894-901.
4. Harvey, A.L., R. Edrada-Ebel, and R.J. Quinn, The re-emergence of natural products for drug discovery in the genomics era. Nature Reviews Drug Discovery, 2015. 14(2): p. 111-129.
5. Sukuru, S.C.K., et al., Plate-based diversity selection based on empirical HTS data to enhance the number of hits and their chemical diversity. Journal of biomolecular screening, 2009. 14(6): p. 690-699.
6. Hert, J., et al., Quantifying biogenic bias in screening libraries. Nature chemical biology, 2009. 5(7): p. 479-483.
7. Newman, D.J. and G.M. Cragg, Natural products as sources of new drugs over the 30 years from 1981 to 2010. Journal of natural products, 2012. 75(3): p. 311-335.
8. Simberloff, D., et al., Impacts of biological invasions: what’s what and the way forward. Trends in ecology & evolution, 2013. 28(1): p. 58-66.
9. Hulme, P.E., et al., Bias and error in understanding plant invasion impacts. Trends in ecology & evolution, 2013. 28(4): p. 212-218.
10. Pimentel, D., R. Zuniga, and D. Morrison, Update on the environmental and economic costs associated with alien- invasive species in the United States. Ecol. Econ., 2005. 52(3): p. 273-288.
11. King, R.E., J.A. Bomser, and D.B. Min, Bioactivity of resveratrol. Comprehensive Reviews in Food Science and Food Safety, 2006. 5(3): p. 65-70.

Post by Dai Fazakerley.
Dai is a PhD student with Prof. Luis Mur and is one of our Biochemistry BSc graduates.

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