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Antifungal and Antileukemic Compounds from Cyanobacteria: Bioactivity, Biosynthesis, and Mechanism of Action

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Antifungal and Antileukemic Compounds from Cyanobacteria: Bioactivity, Biosynthesis, and Mechanism of Action ANTIFUNGAL AND ANTILEUKEMIC COMPOUNDS FROM CYANOBACTERIA: BIOACTIVITY, BIOSYNTHESIS, AND MECHANISM OF ACTION Anu Humisto Department of Microbiology Faculty of Agriculture and Forestry University of Helsinki, Finland ACADEMIC DISSERTATION To be presented, with the permission of the Faculty of Agriculture and Forestry of the University of Helsinki, for public examination in Auditorium I at Info Centre Korona, Viikinkaari 11, on 23rd November 2018, at 12 o'clock noon. Helsinki 2018 Supervisors Professor Kaarina Sivonen Department of Microbiology University of Helsinki, Finland Professor Lars Herfindal Department of Clinical Science University of Bergen, Norway Docent Jouni Jokela Department of Microbiology University of Helsinki, Finland Reviewers Docent Päivi Tammela Division of Pharmaceutical Biosciences Faculty of Pharmacy University of Helsinki, Finland Professor Lena Gerwick Center for Marine Biotechnology and Biomedicine Scripps Institution of Oceanography University of California San Diego, USA Thesis evaluation committee Professor Per Saris Department of Microbiology University of Helsinki, Finland Academy Fellow Miia Mäkelä Department of Microbiology University of Helsinki, Finland Opponent Professor Jeanette H. Andersen Norwegian College of Fishery Science University of Tromsø, Norway Custos Professor Kaarina Sivonen Department of Microbiology University of Helsinki, Finland Dissertationes Schola Doctoralis Scientiae Circumiectalis, Alimentariae, Biologicae Cover: Lake Löytänejärvi (Pori, Finland), light micrograph of Nostoc sp. UHCC 0450, and transmission electron micrograph of MOLM-13 cell organelles. All figures by Anu Humisto. ISSN 2342-5423 (print) ISSN 2342-5431 (online) ISBN 978-951-51-4658-8 (paperback) ISBN 978-951-51-4659-5 (PDF) http://ethesis.helsinki.fi Unigrafia Helsinki 2018 Table of contents LIST OF ORIGINAL PUBLICATIONS .......................................................................... III LIST OF RELATED PUBLICATIONS ............................................................................ IV ABBREVIATIONS ..................................................................................................... V ABSTRACT ............................................................................................................. VI TIIVISTELMÄ ......................................................................................................... VII 1 INTRODUCTION .............................................................................................. 1 1.1 NATURAL PRODUCTS AND THEIR IMPORTANCE ........................................................ 1 1.2 CYANOBACTERIA AND THEIR NATURAL PRODUCTS .................................................... 2 1.3 BIOACTIVITY ..................................................................................................... 4 1.3.1 Anticancer activity ........................................................................................ 5 1.3.2 Antifungal activity ......................................................................................... 9 1.4 BIOSYNTHESIS ................................................................................................ 16 1.4.1 Polyketide synthesis ................................................................................... 17 1.4.2 Nonribosomal peptide synthesis and hybrid synthesis .............................. 18 1.5 MECHANISM OF ACTION ................................................................................... 19 2 STUDY AIMS ................................................................................................. 22 3 SUMMARY OF MATERIALS AND METHODS ................................................... 23 3.1 STRAINS AND CELL LINES USED IN THIS THESIS ........................................................ 23 3.2 SUMMARY OF METHODS .................................................................................. 23 4 SUMMARY OF RESULTS AND DISCUSSION .................................................... 25 4.1 BIOACTIVE CYANOBACTERIAL COMPOUNDS .......................................................... 25 4.1.1 Antileukemic activity (I) .............................................................................. 25 4.1.2 Antifungal or cytotoxic activity (II, IV) ........................................................ 26 4.1.3 Culture collections and screening (I–IV) ..................................................... 29 4.2 DISCOVERING BIOSYNTHESIS PATHWAYS (III) ........................................................ 30 4.3 ELUCIDATING MECHANISM OF ACTION (IV) .......................................................... 3 5 5 CONCLUSIONS AND FUTURE PROSPECTS ...................................................... 39 6 ACKNOWLEDGEMENTS ................................................................................. 41 7 REFERENCES ................................................................................................. 42 I II List of original publications This thesis is based on the following publications: I Humisto A, Herfindal L, Jokela J, Karkman A, Bjørnstad R, Choudhury RR, Sivonen K. 2016. Cyanobacteria as a source for novel anti-leukemic compounds. Current Pharmaceutical Biotechnology, 17(1):78–91. II Shishido TK, Humisto A, Jokela J, Liu L, Wahlsten M, Tamrakar A, Fewer DP, Permi P, Andreote APD, Fiore MF, Sivonen K. 2015. Antifungal compounds from cyanobacteria. Marine Drugs, 13(4):2124–2140. III Humisto A, Jokela J, Liu L, Wahlsten M, Wang H, Permi P, Machado JP, Antunes A, Fewer DP, Sivonen K. 2018. The swinholide biosynthesis gene cluster from a terrestrial cyanobacterium, Nostoc sp. strain UHCC 0450. Applied and Environmental Microbiology, 84(3):e02321-17. IV Humisto A, Jokela J, Teigen K, Wahlsten M, Permi P, Sivonen K, Herfindal L. 2018. Characterization of the membrane interaction of the antifungal and cytotoxic cyclic glycolipopeptide hassallidin. Submitted manuscript. The publications are referred to in the text by their roman numerals. Author's contribution I Anu Humisto participated in the design of the study, performed the experiments, participated in the data analysis, and wrote the first article draft. II Anu Humisto participated in the design of the study, performed part of the ex- periments, and participated in the writing of the manuscript. III Anu Humisto participated in the design of the study, performed the experiments, participated in the data analysis, and wrote the first article draft. IV Anu Humisto participated in the design of the study, performed the experiments, participated in the data analysis, and wrote the first article draft. III List of related publications V Pancrace C, Jokela J, Sassoon N, Ganneau C, Desnos-Ollivier M, Wahlsten M, Humisto A, Calteau A, Bay S, Fewer DP, Sivonen K, Gugger M. 2017. Rearranged biosynthetic gene cluster and synthesis of hassallidin E in Planktothrix serta PCC 8927. ACS Chemical Biology, 12(7):1796–1804. IV Abbreviations A Adenylation domain ACP Acyl carrier protein AML Acute myeloid leukemia AT Acyltransferase domain C Condensation domain cf. sp. Uncertainly defined species DH Dehydratase E Epimerization domain EC50 Half-maximal effective concentration ER Enoyl reductase HGT Horizontal gene transfer IC50 Half-maximal inhibitory concentration IPC-81 Rat acute myeloid leukemia cell line kb Kilo base pairs KS Ketosynthase KS0 Nonelongating ketosynthase KR Ketoreductase LC-MS Liquid chromatography mass spectrometry Mb Mega base pairs MIC Minimum inhibitory concentration MOA Mechanism of action MOLM-13 Human acute myeloid leukemia cell line MT Methyl transferase NMR Nuclear magnetic resonance NRK Normal rat kidney epithelial cell line NRPS Nonribosomal peptide synthetase OMT O-methyl transferase ORF Open reading frame OX Monooxygenase domain PCP Peptidyl carrier protein PKS Polyketide synthase PS Pyran synthase scp Scytophycin gene cluster sp. Species swi Swinholide gene cluster TE Thioesterase domain UHCC University of Helsinki Cyanobacteria Culture Collection V Abstract Nature is a treasury of bioactive natural products that are developed into pharmaceuticals, cosmetics and other industrial applications. Natural products have an impact on all of us, for instance, in the form of antibiotics. Most of the drugs sold today are natural products or their derivatives. However, the need for new natural products has not decreased but is ra- ther increasing. The incidences of certain diseases such as cancers are rising and resistance to treatment is a major problem. Especially prokaryotes and plants produce these intriguing natural products, which display several different bioactivities. Cyanobacteria are photosyn- thetic prokaryotes that belong to the most prolific sources of bioactive compounds. This study expands the knowledge of cyanobacterial natural products, including their activities, biosynthesis, and mechanisms of action. The University of Helsinki Cyanobacteria Culture Collection was utilized in this study. Cultured cyanobacteria were screened for an- tileukemic and antifungal activity using cell assays and disk diffusion analyses. Bioactive compounds were identified with spectrometric methods. The screenings revealed several bioactive hits, including antifungal, antileukemic and cytotoxic activities. Novel compound candidates and known compounds from new habitats or genera were found. In addition, novel variants of known compounds were identified. The results from screening were used to select cyanobacterial strains for whole ge- nome sequencing. Genomic analysis was used to
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