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Thesis Hsf 2020 Watson Daniel John.Pdf Screening of actinobacteria for novel antimalarial compounds Town Daniel John Watson (WTSDAN003) Cape Submitted to the University of Cape Town In fulfilment of the requirementof for the degree: PhD Clinical Pharmacology Faculty of Health Sciences UNIVERSITY OF CAPE TOWN UniversityFebruary 2020 Supervisor: A/Prof Lubbe Wiesner Co-supervisor: Dr Paul Meyers The copyright of this thesis vests in theTown author. No quotation from it or information derived from it is to be published without full acknowledgement of the source. The thesis is to be used for private study or non- commercial research purposes only.Cape Published by the Universityof of Cape Town (UCT) in terms of the non-exclusive license granted to UCT by the author. University DECLARATION It is herewith declared that the work represented in this dissertation/thesis is the independent work of the undersigned (except where acknowledgements indicate otherwise) and has not been submitted at any other University for a degree. In addition, copyright of this thesis is hereby ceded in favour of the University of Cape Town. t5/z/2-02v Date Acknowledgements This thesis is dedicated to my friends and family who gave me the opportunities and support that allowed me to fulfil my dream. Firstly, I would like to thank the NRF and UCT for funding me through my MSc and PhD. Without it, none of this would have been possible. To my supervisor Prof Lubbe Wiesner, thank you for providing me with the opportunity to pursue my interests and passions. Your faith in me and this project kept me going even when I was not sure I could. To my co-supervisor Dr Paul Meyers, thank you for your patience and wisdom. Thank you for helping me learn from my endless mistakes in the lab and while writing. Your voice of reason lead me through more than a few trying times. A special thanks to Prof Peter Smith who taught me to turn a loss into a win and whose wisdom and encouragement meant more than I could ever show. Thank you to my colleagues and friends at the Division of Pharmacology: Alicia, Alek, Anton, Dale, Virgil, Sumaya, Jill, Lloyd, Lizahn, Devasha, Katie, Lucas, and many more, for their help and encouragement. It was a pleasure to work with you all. A special thank you to Dr Joel Rindelaub and Dr Bruno Sacchetto Paulo for helping me with article access and my questions. They really helped turn the project around at crucial stages. Thank you to my colleagues in the Department of Chemistry and Molecular and Cell Biology: Kojo Acquah, Dr Godwin Dziworn, Diana Melis, Sam and Adeebah, for their help with data acquisition and analysis. Thank you to my friends: Bianca, Brad, Chad, Jess, Simone, Rudi, Hanneke, Callen, Kim, John, James, my DnD crew, and the TrueKrav and X wing community, for their support, interest and dealing with me during the good times and bad times. Thank you to my partner Hannah, for her constant love and support, and making me the happiest man in the world. Finally, thank you to my family: Carmen, George and Simon. Without your guidance, unconditional love and faith this never would have happened. I don’t know what I would do without any of you and I love you all. “Success is not final, failure is not fatal: it is the courage to continue that counts” Winston Churchill 3 Abstract The success of our first-line antimalarial treatments is threatened by increased drug resistance in Plasmodium parasites. This makes the development of novel drugs critical to combat malaria. Historically, natural products have been an excellent source of novel antimalarial compounds and thus are an ideal place to search for potential drugs. Filamentous members of the bacterial phylum, Actinobacteria, are well-known antibiotic producers, but their antimalarial potential has not been well investigated. This makes these actinobacteria a potentially valuable source of novel antimalarial compounds. To evaluate the antimalarial potential of the filamentous actinobacteria, uncharacterized environmental actinobacterial strains from the Meyers laboratory culture collection, as well as the type strains of new actinobacterial species identified and characterized in the Meyers laboratory, were screened for antiplasmodial activity against drug-sensitive Plasmodium falciparum, NF54. Liquid cultures were extracted using the mid-polar solvent, ethyl acetate, with the aim of discovering drug-like molecules that can be administered orally. Thirty-one strains of actinobacteria belonging to eight genera (Actinomadura, Amycolatopsis, Gordonia, Kribbella, Micromonospora, Nocardia, Nonomuraea, and Streptomyces) were screened revealing fourteen active strains. Eight strains were identified for further study as the displayed antiplasmodial efficacy matching predefined criteria. Of these eight candidates, Streptomyces strain PR3 was selected, as it showed excellent antiplasmodial efficacy, no cytotoxicity against Chinese Hamster Ovary (CHO) or liver HepG2 cell lines, no haemotoxicity, and was easy to culture. Bioassay-guided fractionation of the crude extracts of strain PR3, supported by high-resolution mass spectrometry (HRMS) and nuclear magnetic resonance (NMR) analysis, was conducted to isolate and identify the compounds responsible for the antiplasmodial activity. During purification by solid phase extraction (SPE), a novel class of compounds was isolated. The structure of these compounds was elucidated by HRMS and NMR analysis and determined to be a series of crown ethers with a methylated backbone. These methylated crown ethers (MCE) were not produced by strain PR3, but by the cyclization of polypropylene glycol (PPG) oligomers from Amberlite® XAD-16N 20–60 mesh resin under aqueous conditions. The MCEs displayed weak antiplasmodial activity against P. falciparum NF54, without cytotoxicity against the Chinese Hamster Ovary, HepG2 cell lines, nor human erythrocytes. To the author’s 4 knowledge, the MCEs are novel compounds, and this is the first time the cyclization of PPG oligomers into crown ethers has been reported. As the MCEs were not responsible for strain PR3’s potent antiplasmodial activity, further study was conducted. Using the Global Natural Product Social molecular networking (GNPS) workflow, genome mining, and NMR analysis, it was revealed that the cyclodepsipeptides, valinomycin, montanastatin, and nine other novel analogues were responsible for the high antiplasmodial activity detected. A review of the literature revealed that the structure of four of these analogues had been predicted, based on MS/MS and the biosynthesis of valinomycin. Using the same described biosynthetic logic and MS/MS analysis, two new cyclodepsipeptides, compounds 1054 and 1068, were elucidated. Unfortunately, chromatographic systems developed were unable to purify the cyclodepsipeptides, and individual evaluation of their antiplasmodial efficacy and host selectivity was not possible. The fraction containing the cyclodepsipeptides exhibited strong antiplasmodial activity against the drug-sensitive, NF54 and multidrug-resistant K1, strains of P. falciparum. No cytotoxicity was displayed against the CHO cell line and no haemotoxicity was seen against human erythrocytes. Moderate toxicity was exhibited against the liver HepG2 cell line; however, the selectivity index of the cyclodepsipeptides suggested that they are selectively targeting the Plasmodium parasites. Overall, these results are positive, and further study of the individual cyclodepsipeptides is warranted. During the investigation, discrepancies were noticed between different fractions in terms of antiplasmodial activity. These fractions contained both the MCEs and, cyclodepsipeptides along with a range of impurities, yet they displayed potent antiplasmodial activity. Further study suggested that combination of the MCEs and cyclodepsipeptides elicits a synergistic response and improves antiplasmodial efficacy. This was determined independently using two models, the fixed-ratio isobologram method and the CompuSyn programme based on the mass- action law principle. The workflow developed during this investigation demonstrates how new technologies can be used to dereplicate and elucidate bioactive natural products. This workflow can be utilized to continue this research and identify new natural products that can combat malaria. 5 List of Abbreviations ACT Artemisinin based Combination Therapy APAD 3-acetyl pyridine BCCM Belgian Co-Ordinated Collection of Microorganisms BGC Biosynthetic Gene Cluster bp base pairs CCC counter current chromatography CE collision energy CHO Chinese Hamster Ovary CI combination index CM complete medium COSY correlation spectroscopy CSP circumsporozoite protein CZ Czapek Solution Agar DDT dichloro-diphenyl-trichloroethane DHA dihydroartemisinin DHFR dihydrofolate reductase DHPS dihydropteroate synthetase DMEM Dulbecos Modified Eagles Medium DMSO dimethyl sulfoxide DNDi Drugs for Neglected Disease initiative DSMZ #553 German Culture Collection medium #553 6 EtAc ethyl acetate FCS foetal calf serum FDA Food and Drug Administration FIC50 fractional IC50 FT-IR Fourier Transform Infrared Radiation GC gas chromatography GDP gross domestic product GIT gastrointestinal tract GMEP Global Malaria Eradication Programme GNPS Global Natural Product Social Molecular Networking Hiv α-hydroxyisovaleric acid HM Hacène’s Medium HMBC heteronuclear multiple-bond coherence HPLC high performance liquid chromatography HRMS high-resolution mass spectrometry HTS high throughput screening IC50 half maximal inhibitory concentration IDA information-dependent acquisition IPT intermittent
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