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Deciphering New Nonribosomal Peptide Synthetases and Their

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Deciphering New Nonribosomal Peptide Synthetases and Their UNIVERSITY OF LILLE 1 SCIENCE AND TECHNOLOGY PhD THESIS Thesis presented for the degree of Philosophiae Doctor by Qassim Abdullah Ahmed ESMAEEL Major: BIOLOGICAL ENGINEERING ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ Deciphering new nonribosomal peptide synthetases and their products from genomic data ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ No: 42071 Charles Viollette Institute Polytech’Lille, France 8 July 2016 Monique Royer, Researcher-HDR (CIRAD, Montpellier, France) Reviewer Pierre Cornelis, Professor (University of Brussels, Belgium) Reviewer Monica Höfte, Professor (Université of Ghent, Belgium) Examinator Jean-Luc Pernodet, Professor (CNRS, University of Paris-Sud, France) Examinator Maude Pupin, Assistant Professor -HDR (University of Lille 1, France) Examinator Philippe Jacques, Professor (Université of liège, Belgium) Co-Supervisor Valérie Leclère, Assistant Professor - HDR (University of Lille 1, France) Supervisor UNIVERSITE DE LILLE 1 SCIENCES ET TECHNOLOGIES THESE Présentée par Qassim Abdullah Ahmed ESMAEEL Pour l’obtention du grade de DOCTEUR DE L’UNIVERSITE DE LILLE 1 Filière: INGENIERIE DES FONCTIONS BIOLOGIQUES ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ Identification de nouvelles synthétases non ribosomiques et de leurs produits à partir de données de génomique ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ N° Ordre: 42071 Préparée à l’Institute Charles Viollette Polytech’lille, France Soutenance le 8 juillet 2016 devant le jury composé de: Monique Royer, Directrice de recherche- HDR (CIRAD, Montpellier, France) Rapporteur Pierre Cornelis, Professeur (Université de Bruxelles, Belgique) Rapporteur Monica Höfte, Professeur (Université de Gand, Belgique) Examinatrice Jean-Luc Pernodet, Professeur (CNRS, université paris-sud, France) Examinateur Maude Pupin, Maitre de conférences- HDR (Université de Lille 1, France) Examinatrice Philippe Jacques, Professeur (Université de liège, Belgique) Co-directeur Valérie Leclère, Maitre de conférences- HDR (Université de Lille 1, France) Directrice Dedication To my beloved family With love and gratitude Acknowledgement Words fail me to express how much I am indebted to my supervisor Dr. Valerie Leclère for giving me the opportunity to conduct this research. She provided invaluable support and unflinching encouragement throughout this period. My mere expression of thanks likewise does not suffice for her patience during all the meetings, discussions and continuous interest in supervising me. I am very grateful to my co supervisor Prof. Philippe Jacques for his relentless scientific guidance, motivation, discussions during my thesis. I would like to thank Prof. Pascal for allowing me to work in his laboratory and provided me with assistance throughout my studies. I would like to thank Dr. Monique Royer and Prof. Pierre Cornelis for reviewing my thesis and Prof. Monica Höfte, Dr. Maude Pupin, and Prof. Jean-Luc Pernodet for serving on my examination committee. Big thanks to Dr. Max Béchet for his unlimited help and cooperation during throughout my studies. I am indebted to the Sanaa University, Yemen for providing partial funding for my PhD in Lille1 University, France. My thanks to my friends and colleagues for the great time I had in our group. I enjoyed the atmosphere, their friendship, and their support. My thanks to Yazen, Alaa, Ameen, Oumayma, Sabrine, Amel, Kalim, Lamia, Samiha, Rémi, Juliette, Alexandra, Debarun, Alexandre, Sandy, Justine, Ahmed, Michael, Amirouche, Marwan, Adil, Louis, Mohammed, Antoine, Delphine, Alexandre, Cyril, Maxim, Gabrielle and Delphine Caly for the great collaboration over the years. Special thanks to Amjed, Suhaib, Mouad, Muaamer, Yahya, and Ameen Berdouz for their support during my study. It was a pleasure to work with friends and colleagues from laboratory of Phytopathology, university of Ghent, Belgium, to benefit from their knowledge. Especially, I would like to thank Dr. Nam Phuong Kieu for the interesting help and fruitful discussions. Last, but not least, I would like to thank my great Mum, Father, brothers and sisters for their support and prayers. Of greatest value to me was the tireless help, encouragement and support of my beloved wife Nadya and the patience and cooperation of my lovely daughter Ruba. I) Publications that were done during this thesis 1: Qassim Esmaeel, Mickael Chevalier, Gabrielle Chataigné, Rathinasamy Subashkumar, Philippe Jacques and Valérie Leclère, Nonribosomal peptide synthetase with a unique iterative- alternative-optional mechanism catalyzes amonabactin synthesis in Aeromonas. Appl Microbiol Biotechnol (2016). doi:10.1007/s00253-016-7773-4 2:Qassim Esmaeel, Maude Pupin, Nam Phuong Kieu, Gabrielle Chataigné, Max Béchet, Jovana Dervael, François Krier, Monica Höfte, Philippe Jacques and Valérie Leclère, 2016. Burkholderia genome mining for nonribosomal peptide synthetases reveals a great potential for novel siderophores and lipopeptides synthesis. Microbiology open. doi:10.1002/mbo3.347 3: Maude Pupin, Qassim Esmaeel, Areski Flissi, Yoann Dufresne, Philippe Jacques, and Valérie Leclère, 2015. Norine: a powerful resource for novel nonribosomal peptide discovery. Synthetic and Systems Biotechnology. doi:10.1016/j.synbio.2015.11.001 4: Qassim Esmaeel, Philippe Jacques, and Valérie Leclère, Non ribosomal peptides and polyketides of Burkholderia as a new source of bioactive compounds potentially implicated in agriculture and pharmaceutical (Review) (In preparation) II) Communications Oral Presentation 1 : Qassim Esmaeel, Philippe Jacques, and Valérie Leclère. Florine and Norine: powerful tools for in silico genome mining leading to discovery of novel nonribosomal peptides. Annual Conference 2016 of Microbiology Society, 21–24 March 2016- Liverpool, UK. 2: Qassim Esmaeel, Maude Pupin, Nam Phuong Kieu, Gabrielle Chataigné, Max Béchet, Jovana Deravel, François Krier, Monica Höfte, Philippe Jacques and Valérie Leclère. Burkholderia genome mining for nonribosomal peptide synthetases reveals a great Potential for novel lipopeptides synthesis. 10th International PGPR Workshop Liège, Belgium, 16-19/06/2015 3: Qassim Esmaeel, Maude Pupin, Nam Phuong Kieu, Gabrielle Chataigné, Max Béchet, Jovana Deravel, François Krier, Monica Höfte, Philippe Jacques and Valérie Leclère. Burkholderia genome mining for nonribosomal peptide synthetases reveals a great Potential for novel lipopeptides synthesis. Journée des doctorants, 21 Novembre 2014, Institut Charles Viollette, Polytech Lille, Lille, France III) Poster: 1 : Qassim Esmaeel, Maude Pupin, Nam Phuong Kieu, Gabrielle Chataigné, Max Béchet, Jovana Deravel, François Krier, Monica Höfte, Philippe Jacques and Valérie Leclère, Burkholderia genome mining for nonribosomal peptide synthetases reveals a great Potential for novel lipopeptides synthesis. The 6th Congress of European Microbiologists (FEMS 2015), 7-11 June 2015, Maastricht, Netherlands. Abstract Microorganisms are considered one of the most important sources of secondary metabolites including ribosomal and non ribosomal peptides. The search of new non ribosomal peptides has been motivated by their wide applications exploited by industries in different area including pharmaceutical and phytosanitary sectors. They are produced through complex synthetases called non ribosomal peptides synthetases. More than 70 % of NRPs have a complex structure that includes one or more cycles and branches. Therefore, development of specific tools dedicated to the screening of these peptides is necessary as they cannot be predicted and analyzed as classical peptides. With the aim to further analyse biosynthesis pathways and to identify new active peptides, I mainly studied two bacterial models: Burkholderia and Aeromonas. The genome-mining is a very powerful approach for the discovery of new non NRPs. Indeed, among 48 strains of Burkholderia, 228 gene clusters containing NRPSs and hybrid NRPS-PKS were found via in silico analysis following Florine workflow. The current study lead to the discovery of new peptides in Burkholderia including a new siderophore named phymabactin and a cyclic lipopeptide we have called burkhomycin. It also gave new insights on the mechanism of nonribosomal synthetases, exemplified by the detection of dual C/E domains in NRPSs involved in the production of cyclic lipopeptides by Burkholderia and the identification of a unique use of domains and modules in the pathway responsible for synthesis of amonabactins in A. hydrophila. 1 Résumé Les micro-organismes sont considérés comme l'une des sources les plus importantes de métabolites secondaires, y compris les peptides ribosomiques et non ribosomiques. La recherche de nouveaux peptides non ribosomiques a été motivée par leurs larges applications dans diverses industries telles que les secteurs pharmaceutiques et phytosanitaires. Ils sont produits par complexes enzymatiques appelés NRPSs. Plus de 70% des peptides non ribosomiques ont une structure complexe qui comprend un ou plusieurs cycles et des ramifications. Par conséquent, le développement d'outils spécifiques dédiés
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