Targeting Natural Products to counter the challenge of MRSA

Abstract

As the global threat of antibiotic resistance grows the approval rate of new antibiotics falls. Pharma companies are dropping their antibiotic research programmes at the time when new antibiotics are needed the most due to antibiotic resistance. Paradoxically antibiotic resistance is one of the many reasons that the discovery of new antibiotics is not lucrative enough for it to be a financially viable pursuit. Promising high-throughput technologies have been unsuccessfully employed to streamline drug discovery due to the lack of novel chemicals within libraries. Natural products have contributed massively to drug discovery in the past although its contribution to the declining number of antibiotics discovered recently has also diminished. To revive the drug discovery pipeline invasive weeds were targeted as a potential source of novel chemical compounds. Three species; Fallopia japonica, Impatiens glandulifera and Rhododendron ponticum were collected. Each species was extracted and fractioned to discover any potential antimicrobial compounds. A particularly active compound 2-methoxy-1,4naphthoquinone (MNQ) was discovered. This compound was found to have a broad range of activity against clinically relevant bacteria. The methoxy group was found to be crucial for the potent antimicrobial activity of this compound. It was also a potent inhibitor of Schistosoma mansoni. Cytotoxicity of this compound was found to be a potential issue with mixed results. High throughput metabolomic methodologies were developed to understand the mechanism by which MNQ inhibits the growth of MRSA. The metabolomic effect of MNQ was compared to other antibiotics, it was found that MNQ had a distinctive metabolomic effect. This unique effect was further investigated with in-depth metabolic pathway analysis using statistical methods twinned with KEGG metabolomics pathway database. Once a tentative mode of action was identified transmission electron microscopy and specific antimicrobial assays were used to support this theory. This research project has discovered a promising antimicrobial and anthelminthic compound and the developed metabolomic methodology yielded a large amount of useful data regarding the mode of action of MNQ and other antibiotics.

Date of Award	2020
Original language	English
Awarding Institution	Aberystwyth University
Supervisor	Luis Mur (Supervisor) & Ifat Parveen Shah (Supervisor)