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Using synthetic biology to harness biopharmaceuticals from microorganisms

Primary Supervisor: Dr Fabrizio Alberti, School of Life Sciences

Secondary supervisor: Dr Christophe Corre

PhD project title: Harnessing biopharmaceuticals from microorganisms

University of Registration: University of Warwick

Project outline:

Background

Most of the bioactive molecules used in agriculture and medicine are made by microorganisms. For instance, penicillin and cephalosporin antibiotics come from fungi and represent together 47% ($19.8 billion) of the global antibiotic market. Traditionally, these and other natural products are isolated from their naturally producing sources, involving costly extraction procedures. The use of alternative (heterologous) hosts can improve the production of microbial-derived biopharmaceuticals, as well as help revealing the enzymatic pathways that govern their assembly.1

Objectives

Work in the Alberti lab focuses on understanding how specific biopharmaceuticals, such as antimicrobials and anticancer molecules, are made by microorganisms and improve their biosynthesis.2–4

The main objectives of the PhD project will be:

  • To understand the molecular basis of the enzymatic pathway for a specific biopharmaceutical of interest.
  • To reconstitute the enzymatic pathway of interest in an industrially relevant heterologous host, such as Saccharomyces cerevisiae and Aspergillus oryzae, and to improve production titres.

Methods

This is a multidisciplinary PhD project that will allow the student to develop knowledge in various disciplines.

  1. Bioinformatics: genomic and transcriptomic data will be analysed through bioinformatic tools, in order to pinpoint genes of interest that will then be characterised experimentally.
  2. Molecular Biology: Golden Gate assembly, Gibson assembly and yeast-based homologous recombination will be used to clone the genes of interest and assemble them into suitable expression vectors.
  3. Genetic Engineering: heterologous expression of the genes of interest will allow to recreate and elucidate the enzymatic pathway in cerevisiae and A. oryzae. Genetic engineering will be performed (e.g. through CRISPR/Cas9) with the aim to improve the production of the biopharmaceutical of interest.
  4. Analytical Chemistry: Metabolic analyses will be performed in order to characterise the natural product intermediates and define the catalytic function of the enzymes involved in the pathway.

References:

https://www.alberti-lab.com/

  1. Alberti, F.; Foster, G. D.; Bailey, A. M. Natural Products from Filamentous Fungi and Production by Heterologous Expression. Appl. Microbiol. Biotechnol. 2017, 101 (2), 493–500. https://doi.org/10.1007/s00253-016-8034-2.
  2. Alberti, F.; Khairudin, K.; Venegas, E. R.; Davies, J. A.; Hayes, P. M.; Willis, C. L.; Bailey, A. M.; Foster, G. D. Heterologous Expression Reveals the Biosynthesis of the Antibiotic Pleuromutilin and Generates Bioactive Semi-Synthetic Derivatives. Nat. Commun. 2017, 8, 1831. https://doi.org/10.1038/s41467-017-01659-1.
  3. Alberti, F.; Leng, D. J.; Wilkening, I.; Song, L.; Tosin, M.; Corre, C. Triggering the Expression of a Silent Gene Cluster from Genetically Intractable Bacteria Results in Scleric Acid Discovery. Chem. Sci. 2019, 10 (2), 453–463. https://doi.org/10.1039/c8sc03814g.
  4. Kaur, D.; Corre, C.; Alberti, F. Engineering Isoprenoid Quinone Production in Yeast. bioRxiv 2020, 2020.02.06.932020. https://doi.org/10.1101/2020.02.06.932020.

BBSRC Strategic Research Priority: Renewable Resources and Clean Growth: Industrial biotechnology

Techniques that will be undertaken during the project:

  • Genomic and transcriptomic analyses
  • Bioinformatic analyses of microbial genomes and gene clusters
  • PCR, gene cloning, CRISPR/Cas9 and other molecular biology techniques
  • Generation of engineered microbial strains
  • Liquid chromatography-mass spectrometry (LC-MS)
  • Nuclear magnetic resonance (NMR) spectroscopy

Typical pattern of working hours:

  • 35 hrs per week with flexible working arrangements

Contact: Dr Fabrizio Alberti, University of Warwick