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Harnessing 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, Abamectin derives from actinomycete bacteria and is one of the most widely used insecticides in crop protection, with a global market of $938 million every year. Similarly, 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.

Objectives: Work in the Alberti lab focuses on understanding how specific biopharmaceuticals, such as antimicrobials and anticancer molecules, are made by microorganisms, i.e. higher fungi and actinomycete bacteria, and improve their biosynthesis.1,2

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 cerevisiaeand Aspergillus oryzae(for fungal-derived biomolecules) or Streptomyces coelicolor (for actinomycete-derived biomolecules).
  • To rewire the metabolism of the heterologous host in order to improve production of the biopharmaceutical of interest.

Methods: This multidisciplinary PhD project will allow the student to develop knowledge in the fields of molecular and synthetic biology, microbial genomics and analytical chemistry.

Genomic and transcriptomic data will be generated for the microorganism of interest and subjected to bioinformatic analyses, in order to pinpoint genes and gene clusters putatively involved in the pathway under study. Gene cloning techniques, such as 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 for the chosen heterologous host. Heterologous expression of the genes of interest will allow to recreate and elucidate the enzymatic pathway in an industrially relevant microorganism, e.g. S. cerevisiae, A. oryzaeor S. coelicolor. Metabolic analyses will be performed in order to characterise the reaction products and define the catalytic function of the enzymes. Genetic engineering will be performed (e.g. through CRISPR/Cas9) with the aim to improve the production of the biopharmaceutical of interest.

References:

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

  1. Alberti F. et al.(2017) Heterologous expression reveals the biosynthesis of the antibiotic pleuromutilin and generates bioactive semi-synthetic derivatives. Nature Communications8: 1831. doi: 10.1038/s41467-017-01659-1.
  2. Alberti F. et al.(2019) Triggering the expression of a silent gene cluster from genetically intractable bacteria results in scleric acid discovery. Chemical Science10 (2): 453-463. doi: 10.1039/C8SC03814G.

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

Contact: Dr Fabrizio Alberti, University of Warwick