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Elucidating and exploiting molecular mechanisms of bacterial antibiotic biosynthesis

Primary Supervisor: Professor Greg Challis, Department of Chemistry

Secondary supervisor: Dr Lona Alkhalaf

PhD project title: Elucidating and exploiting molecular mechanisms of bacterial antibiotic biosynthesis

University of Registration: University of Warwick

Project outline:

Antibiotics are an essential part of modern medicine, but antimicrobial resistance (AMR) is rapidly neutralising their effectiveness. There is thus an urgent need to develop new antibiotics to overcome the health threat posed by AMR. Most clinically used antibiotics derive from microbial natural products, which are often challenging to produce or modify by chemical synthesis.

Our research program focuses on three key themes: 1) the discovery of novel antibiotics from diverse microorganisms, 2) elucidating the molecular mechanisms for antibiotic assembly in microbial cells, and 3) biosynthetic engineering to produce novel antibiotic derivatives with enhanced therapeutic potential. We employ a highly interdisciplinary approach, combining microbiology, molecular genetics, genomics, bioinformatics, enzymology, structural biology, analytical chemistry and organic synthesis, to address these problems.
In recent research, we have discovered antibiotics with promising activity against Mycobacterium tuberculosis, which is responsible for millions of deaths every year in the developing world, and Acinetobacter baumannii, identified by the World Health Organisation as one of three “critical priority” pathogens for new antibiotic research and development. We have also elucidated keys steps in the biosynthesis of several antibiotics, including gladiolin (active against multi-drug resistant M. tuberculosis), enacyloxin IIa (active against carbapenem-resistant A. baumannii), bottromycin (active against methicillin-resistant Staphyloccocus aureus) and pentamycin (registered for the treatment of infections caused by Candida albicansand Trichomonas vaginalis). We have exploited the knowledge gained to create novel analogues of several of these antibiotics, providing insights into their structure-activity relationships and producing potent derivatives that constitute a starting point for the development of new medicines.

References:

  1. J. Masschelein, P.K. Sydor, C. Hobson, R. Howe, C. Jones, D.M. Roberts, Z.L. Yap., J. Parkhill, E. Mahenthiralingam and G.L. Challis. A dual transacylation mechanism for polyketide synthase chain release in enacyloxin antibiotic biosynthesis. Nat. Chem. 2019, 11, 906-912.
  2. S. Kosol, A. Gallo, D. Griffiths, T.R. Valentic, J. Masschelein, M. Jenner, E.L.C de los Santos, L. Manzi, P.K. Sydor, D. Rea, S. Zhou, V. Fulop, N.J. Oldham, S.-C. Tsai, G.L. Challis and J.R. Lewandowski. Structural basis for chain release from the enacyloxin polyketide synthase. Nat. Chem.2019, 11, 913-923.

BBSRC Strategic Research Priority: Understanding rules of life: Microbiology & structural biology, Renewable Resources and Clean Growth: Industrial biotechnology, Integrated understanding of health: Pharmeceuticals

Techniques that will be undertaken during the project:

  • Organic synthesis
  • Bioinformatics
  • Recombinant protein overproduction and purification
  • Antimicrobial activity assays, including MIC determination
  • Small molecule structure elucidation using NMR and CD spectroscopy
  • High resolution mass spectrometry of small molecules and proteins
  • LC-MS analysis of microbial metabolites and enzymatic reaction products
  • X-ray crystallographic analysis of proteins
  • Semi-preparative HPLC purification of natural products and enzymatic reaction products

Contact: Professor Greg Challis, University of Warwick