Antibacterial prenylated isoflavonoids and stilbenoids PDF
Preview Antibacterial prenylated isoflavonoids and stilbenoids
Propositions 1. The site of action of antibacterial prenylated phenolic compounds is the cytoplasmic membrane. (this thesis) 2. After hydrophobicity, molecular shape is the most important feature of antibacterial prenylated phenolic compounds. (this thesis) 3. Evaluation of assumptions advances science more than their prolonged use. 4. Personalized medicine may be effective, but not efficient. 5. “Carbon neutrality” is at its best a delayed “carbon correction”. 6. The current use of referenda in the EU does not serve democracy. 7. Confirmation bias flourishes in the social media environment. Propositions belonging to the thesis entitled: “ANTIBACTERIAL PRENYLATED ISOFLAVONOIDS AND STILBENOIDS Quantitative structure-activity relationships and mode of action.” Carla M. Araya-Cloutier Wageningen, 13 April 2017 Antibacterial prenylated isoflavonoids and stilbenoids Quantitative structure-activity relationships and mode of action Carla Araya-Cloutier Thesis committee Promotors Prof. Dr H. Gruppen Professor of Food Chemistry Wageningen University & Research Co-promotors Dr J-P. Vincken Associate professor, Laboratory of Food Chemistry Wageningen University & Research Dr H.M.W. den Besten Associate professor, Laboratory of Food Microbiology Wageningen University & Research Other members Prof. Dr J.T. Zuilhof, Wageningen University & Research Prof. Dr O.P. Kuipers, University of Groningen Prof. Dr B.H. ter Kuile, University of Amsterdam Prof. Dr P.J.G.M. de Wit, Wageningen University & Research This research was conducted under the auspices of the Graduate School VLAG (Advanced studies in Food Technology, Agrobiotechnology, Nutrition and Health Sciences). Antibacterial prenylated isoflavonoids and stilbenoids Quantitative structure-activity relationships and mode of action Carla Araya-Cloutier Thesis submitted in fulfilment of the requirements for the degree of doctor at Wageningen University by the authority of the Rector Magnificus, Prof. Dr A.P.J. Mol, in the presence of the Thesis Committee appointed by the Academic Board to be defended in public on Thursday 13 April 2017 at 11 a.m. in the Aula. Carla Araya-Cloutier Antibacterial prenylated isoflavonoids and stilbenoids Quantitative structure-activity relationships and mode of action, 200 pages. PhD thesis, Wageningen University, Wageningen, the Netherlands (2017) With references, with summary in English ISBN 978-94-6343-036-4 DOI 10.18174/400170 Abstract Prenylated phenolic compounds, i.e. those bearing a C -isoprenoid (prenyl) substituent, 5 are abundant in plants from the Fabaceae (legume) family and are potential natural antibacterial agents against resistant pathogenic bacteria. To understand the antibacterial properties of these compounds, (quantitative) structure-activity relationships and mode of action of these molecules were investigated against Gram positive and negative bacteria. Compounds belonging to the flavonoid, isoflavonoid and stilbenoid classes were studied. Antibacterial activity was modulated by the (sub)class of phenolic compound, as well as by the configuration, position and number of prenyl groups. Prenylated isoflavones were found to be better antibacterials than prenylated pterocarpans and prenylated stilbenoids. It was also shown that chain prenylation increased the antibacterial activity more than pyran-ring prenylation. Diprenylated compounds were among the most active antibacterials with minimum inhibitory concentrations of less than 10 µg/mL against Listeria monocytogenes. The main molecular characteristics defining antibacterial activity were molecular shape (including flexibility and globularity) and hydrophobicity. Regarding the mode of action of these compounds, it was shown that prenylated phenolic compounds can disrupt the integrity of the membrane by permeabilization very quickly. Interestingly, some good antibacterial prenylated (iso)flavonoids showed good permeabilization capacity whereas others not (including diprenylated molecules), highlighting potential differences in their interactions with the bacterial membrane. Likewise, it was shown that Gram negative intrinsic resistance towards prenylated phenolic compounds is primarily due to the activity of efflux pump systems and that it can be overcome by using an efflux pump inhibitor in combination with antibacterial prenylated compounds. Last, in vitro production of prenylated phenolic compounds was performed with microbial prenyltransferase SrCloQ and novel C- and O-prenylated compounds were produced. Table of contents Chapter 1 General Introduction 1 Chapter 2 The position of prenylation of isoflavonoids and 29 stilbenoids from legumes (Fabaceae) modulates the antimicrobial activity against Gram positive pathogens Chapter 3 Rapid membrane permeabilization of Listeria 65 monocytogenes and Escherichia coli induced by prenylated phenolic compounds: influence of skeleton structure and prenyl configuration Chapter 4 QSAR-based molecular signatures of prenylated 97 (iso)flavonoids underlying antimicrobial potency against and membrane-disruption in Gram positive and Gram negative bacteria: Listeria monocytogenes and Escherichia coli Chapter 5 Structural basis for non-genuine phenolic acceptor 135 substrate specificity of Streptomyces roseochromogenes prenyltransferase CloQ from the ABBA/PT-barrel superfamily Chapter 6 General Discussion 161 Summary 189 Acknowledgments 193 About the author 197
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