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Activation of a Silent Type I Polyketide Synthase Gene Cluster In Activation of a silent type I polyketide synthase gene cluster in Streptomyces ambofaciens ATCC23877 : isolation and characterization of a novel giant macrolide Luisa Laureti To cite this version: Luisa Laureti. Activation of a silent type I polyketide synthase gene cluster in Streptomyces ambo- faciens ATCC23877 : isolation and characterization of a novel giant macrolide. Genomics [q-bio.GN]. Université Henri Poincaré - Nancy 1, 2010. English. NNT : 2010NAN10001. tel-01748223 HAL Id: tel-01748223 https://hal.univ-lorraine.fr/tel-01748223 Submitted on 29 Mar 2018 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. AVERTISSEMENT Ce document est le fruit d'un long travail approuvé par le jury de soutenance et mis à disposition de l'ensemble de la communauté universitaire élargie. Il est soumis à la propriété intellectuelle de l'auteur. Ceci implique une obligation de citation et de référencement lors de l’utilisation de ce document. D'autre part, toute contrefaçon, plagiat, reproduction illicite encourt une poursuite pénale. Contact : [email protected] LIENS Code de la Propriété Intellectuelle. articles L 122. 4 Code de la Propriété Intellectuelle. articles L 335.2- L 335.10 http://www.cfcopies.com/V2/leg/leg_droi.php http://www.culture.gouv.fr/culture/infos-pratiques/droits/protection.htm Faculté des Sciences- UFR Sciences et Techniques Biologiques Ecole Doctorale BioSE : Biologie, Santé, Environnement Thèse présentée et soutenue publiquement pour l’obtention du titre de Docteur de l’Université Henri Poincaré en Sciences de la Vie et de la Santé par Luisa LAURETI Activation of a silent type I polyketide synthase gene cluster in Streptomyces ambofaciens ATCC23877: isolation and characterization of a novel giant macrolide Activation d’un cluster de gènes de polycétide synthase de type I chez Streptomyces ambofaciens ATCC23877 : isolation et caractérisation d’un nouveau macrolide géant Soutenance publique prévue le 7 janvier 2010 devant la commission d’examen : Membres du jury : Rapporteurs : M. Mervyn BIBB Professeur, John Innes Center, Norwich M. Jean-Luc PERNODET Directeur de Recherche CNRS, Université Orsay Examinateurs : M. Frédéric BOURGAUD Professeur, Nancy-Université M. Bernard DECARIS Professeur, Nancy-Université M. Pierre LEBLOND Professeur, Nancy-Université (Directeur de thèse) M. Bertrand AIGLE Maître de Conférences, Nancy-Université Laboratoire de Génétique et Microbiologie UMR INRA-UHP 1128 Faculté des Sciences et Techniques – 54506 Vandœuvre-lès-Nancy The Fishermen know that the sea is dangerous and the storm terrible, but they have never found these dangers sufficient reason for remaining ashore. (Vincent van Gogh) ACKNOWLEDGEMENTS/REMERCIEMENTS Je remercie le Professeur Pierre Leblond pour m’avoir accueillie au sein du Laboratoire de Génétique et Microbiologie et pour m’avoir permis d’entreprendre cette thèse. I would like to thank Professor Mervyn Bibb and Professor Jean-Luc Pernodet for accepting to be my referees. For me it has been a great honour and I hope for them it will be a pleasure to read this thesis. Je voudrais aussi remercier le Professeur Frédéric Bourgaud et le Professeur Bernard Decaris pour avoir accepté d’être mes examinateurs. I would like to thank Professor Greg Challis and the Dr Lijiang Song and Dr Christophe Corre for welcoming me in the lab and for all the precious help in the discovery and the characterization of sambomycin, our “little baby”. I really learned a lot from them and I enjoyed my staying in England very much. Je tiens surtout à remercier mon “dear boss” (☺) le Docteur Bertrand Aigle qui a toujours cru en moi et dans ce projet, même quand moi je n’y croyais plus ! Merci pour la confiance que tu m’as accordée tout au long de cette thèse et pour tous tes conseils professionnels, mais aussi personnels. Merci d’avoir accepté mon « sacré caractère » de petite Calimero et d’avoir été toujours très compréhensible et disponible avec moi ! J’ai beaucoup appris de toi. Ton enthousiasme et ta rigueur scientifique resteront toujours un exemple pour moi. Enfin, travailler côte à côte avec toi a été un vrai plaisir et je sais que tout ça va beaucoup me manquer. Cette thèse n’aurait jamais été achevée sans l’aide et le soutien de toutes les personnes que j’ai eu la chance de rencontrer à Nancy et de celles qui faisaient déjà partie de ma vie. Je suis devenue celle que je suis aussi grâce à eux ! Tout d’abord, je tiens à remercier de tout mon coeur l’équipe Streptomyces ☺ : Laurence, pour sa gentillesse infinie et pour tous les petits moments de bonheur et de pause thé partagés avec moi. Je me suis sentie en famille avec toi, Christophe et les enfants ! Robert, un grand merci à toi pour ton aide à la paillasse et pour ta patience à répondre à mes questions et à mes doutes. Un grand merci également pour avoir été mon partenaire de badminton et de danse, on s’est beaucoup éclatés ensemble. Sans toi le labo n’a plus été pareil ! Merci à Caths, toujours pleine de bonne humeur, d’énergie et toujours disponible envers les autres… promets-moi d’apprendre à dire non de temps en temps ! ;-) Thanks a lot to Isolde, the other foreign English speaking in the lab ! Even if we met at the end of this adventure, we had the chance to share a lot of nice and funny moments and I wish you all the best for your future! Merci à Annabelle, pour son accueil chaleureux et pour son aide à chercher mon petit coin douillet, sans même me connaître auparavant ! Merci pour m’avoir laissée faire du babysitter au petit Daniel, j’ai vraiment aimé ! Je tiens aussi à remercier toutes les autres personnes du laboratoire présentes, passées ou venant juste d’arriver, avec qui j’ai eu le plaisir de partager ces trois années de thèse et qui m’ont permis de ne pas trop sentir la solitude et la distance avec mon pays et mes proches. En particulier, merci à Catherine, Virginie, Séverine, Céline, Xavier et Stéphane pour toutes les petites soirées gourmandes et arrosées passées ensemble. Merci à mes « collègues » thésards Nico, Ludo et Romain à qui je souhaite très bon courage ! Merci aux « petits » du labo (comme je les appelle amicalement) Julien, Aurore, Emilie, Fabien, Justine et Maxime car ils contribuent à rendre le labo très sympa et rigolo! Merci à Sophie pour son super talent d’organisation ! Merci enfin à Fred et Julie, mes deux amis en dehors du labo, avec qui j’ai passé des moments très sympas, oubliant pour quelques heures mon boulot ! A special thank to my dear friend Bjørn, who has always been there for me for better or for worse, even being across the ocean as proof that nothing can ruin our friendship! Thank you very much for reading and correcting my manuscript, you gave me very useful advices and comments, but most of all you always encouraged me in my work because you know how silly I can be when an experiment doesn’t work as I want!! Waar ik ook heen zal gaan, ik zal je altijd in mijn hart dragen. Un grazie infinito ai miei cari amici italiani Gi, Valentina e Laura che sono sempre riusciti a infondermi coraggio e fiducia e che per dimostrarmi il loro affetto sono venuti fino a Nancy! ☺ E infine voglio ringraziare la mia famiglia che mi ha sostenuto per tutto questi anni, standomi sempre vicino e facendomi sentire il loro affetto incondizionato. Se sono quella che sono, lo devo soprattutto a voi e all’esempio di amore, rispetto, altruismo e professionalità che mi avete sempre dato. INDEX ABBREVIATIONS__________________________________________________________________1 INTRODUCTION__________________________________________________________________ 3 1. General context___________________________________________________________________5 2. Secondary metabolism and microbial natural products__________________________________7 2.1 Interconnection between primary and secondary metabolism_______________________________ 9 2.2 The antibiotics___________________________________________________________________10 2.3 Mechanisms of bacterial resistance___________________________________________________12 2.3.1 Active-efflux pumps______________________________________________________ 12 2.3.2 Enzymatic inactivation of the antibiotic_______________________________________ 13 2.3.3 Modification of the target site _______________________________________________13 3. Strategies to discover novel natural bioactive molecules_________________________________14 3.1 Genome mining __________________________________________________________________15 3.1.1 OSMAC approach ________________________________________________________16 3.1.2 Genomisotopic approach ___________________________________________________16 3.1.3 Gene inactivation and comparative metabolic profiling approach ___________________17 3.1.4 Heterologous expression ___________________________________________________18 3.1.5 Modification of the regulatory network________________________________________19 3.2 Metagenomics ___________________________________________________________________20 3.3 Combinatorial biosynthesis _________________________________________________________21
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