Engineering de novo production of chlorinated polyketides in Pseudomonas putida

Descrizione del progetto

Catalizzatori efficienti con batteri vivi per nuovi precursori di farmaci

Lo sviluppo economico sostenibile richiede nuovi biocatalizzatori. I composti alogenati, prodotti chiave con molteplici attività e applicazioni biologiche, vengono ottenuti esclusivamente tramite chimica tradizionale. L’alogenazione selettiva è una strategia chiave per modificare le proprietà dei farmaci. Attualmente, il 30 % dei farmaci utilizzati negli studi clinici è alogenato e l’85 % di tutti gli agenti farmaceutici coinvolge il cloro. Il progetto DONNA, finanziato dall’UE, mira alla produzione biologica di metaboliti clorurati mediante ingegneria metabolica del batterio modello Pseudomonas putida. Verrà stabilita una tabella di marcia verso una versione ricondizionata del microrganismo. I metaboliti clorurati verranno incanalati in polichetidi di nuova natura da enzimi polichetide sintetasi riprogrammati. Il portafoglio di molecole alogenate di queste fabbriche di cellule contribuirà alla bioeconomia europea basata sulla conoscenza, migliorando la competitività e avvantaggiando la società nel suo insieme.

Obiettivo

Sustainable economic development requires new biocatalysts to carry out novel, selective synthesis reactions in an environmentally-friendly fashion. Halogenated organic compounds, key products due to their multiple biological activities and industrial applications, continue to be produced via traditional chemistry and their efficient and cost-effective biosynthesis has not been yet achieved. In the present project, rooted in Metabolic Engineering and Synthetic Biology approaches, I will undertake a complete genetic and metabolic engineering of the model bacterium Pseudomonas putida KT2440 to create a platform for the bio-based production of chlorinated polyketides à la carte, which will contribute to the design of new drug analogues. I will establish and implement a clear roadmap from the extant bacterium to a re-factored version of the microorganism capable of efficiently producing chlorinated precursors, which will be channeled to the synthesis of new-to-nature chlorinated polyketides by reprogrammed modular polyketide synthases enzymes. Furthermore, the broad portfolio of halogenated molecules that can be synthetized with the cell factories from this project will contribute to the European knowledge-based bio-economy, enhance the EU's competitiveness in White Biotechnology and benefit the society as a whole. From a personal perspective, the implementation of this challenging and innovative project in The Novo Nordisk Foundation Center for Biosustainability (DTU Biosustain, the ideal scientific environment to pursue the tasks of DONNA), under the supervision of Dr. Pablo I. Nikel (an expert in the field of Metabolic Engineering of Pseudomonas), will be an unbeatable opportunity for both my professional and personal development. My solid scientific background, on the other hand, ensures a smooth progression as an independent researcher in the field of Metabolic Engineering that will result in a win-win situation for myself and the receiving laboratory.