Old cures for new wounds: Virulence inhibitors from Brazilian pepper Pubblico
Muhs, Amelia (2015)
Abstract
Traditional medical remedies are not always well understood despite their persistent use over centuries to safely and effectively treat a variety of ailments. One such example of this is the anti-infective application of Schinus terebinthifolius, more commonly known as peppertree, for the treatment of wounds. With the decreased efficacy of many antibiotics in the face of growing drug resistance, it is necessary to identify and develop alternative or complementary therapies. As a result of increased knowledge of chemical synergy and bioactivity of natural products, plants are increasingly being investigated as leads for new drugs. Schinus terebinthifolius provides a valuable opportunity for the isolation of bioactive compounds as its use in Brazilian traditional medicine to treat a variety of ailments, including wounds and skin infections, has been well documented. The anti-infective activity of S. terebinthifolius suggests that it may be a source of bioactive compounds that could be used to develop alternative or adjuvant therapies in the treatment of invasive Methicillin Resistant Staphylococcus aureus (MRSA) infections, listed among the top "serious threats" to human health in the USA. Specifically, plant compounds may be able to inhibit the accessory gene regulator (agr) pathway of S. aureus, which is critical in quorum sensing and toxin production. Bioactivity-guided fractionation techniques were employed to prepare a refined extract of S. terebinthifolius fruits (430D-F5) with potent quorum quenching activity in the absence of growth inhibition at concentrations as low as 2 µg/mL. Inhibitory effects of 430D-F5 were confirmed at the transcriptional level with the use of agr fluorescent reporter strains of S. aureus as well as at the translational level through quantification of exotoxin production using HPLC. 430D-F5 was characterized to reveal 47 compounds, currently under further individual evaluation for quorum quenching activity and structure elucidation studies by NMR. Low toxicity to human skin cells as well as considerable quorum quenching activity at low doses both corroborate the traditional medical uses of Schinus terebinthifolius to treat skin and soft tissue infections and provide support for further investigation of the plant as an alternative treatment or adjuvant therapy for invasive methicillin resistant S. aureus infections.
Table of Contents
Chapter 1: Introduction (1)
-Natural products as alternative treatments: an ethnobotanical approach to drug discovery
-Project aims and research questions
Chapter 2: Literature Review (4)
-The status of traditional medicine
-An investigation of Schinus terebinthifolius
-Staphylococcus aureus and antimicrobial resistance
Chapter 3: Materials and Methods (31)
-Literature review
-Experimental overview
Chapter 4: Results (44)
Chapter 5: Discussion (56)
-Quorum quenching activity of Schinus terebinthifolius
-Quenching without killing: a unique approach to drug development
-Synergistic chemistry: treating infectious diseases with natural products
-Future directions
-Conclusion
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