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Discovery, biosynthesis and bioengineering of novel antimicrobials

Primary Supervisor: Professor Greg Challis, Department of Chemistry

Secondary supervisor: Dr Lona Alkhalaf

PhD project title: Discovery, biosynthesis and bioengineering of novel antimicrobials

University of Registration: University of Warwick

Project outline:

Antimicrobials are an essential part of modern medicine, and are also used widely in agriculture, e.g. as fungicides. However, antimicrobial resistance (AMR) is rapidly neutralising their effectiveness. There is thus an urgent need to develop new antibiotics to overcome threats to health and sustainable agriculture posed by AMR. Most antimicrobials used in medicine and agriculture 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 antimicrobials from diverse microorganisms, 2) elucidating the molecular mechanisms for their assembly, and 3) biosynthetic engineering to produce novel derivatives with enhanced therapeutic and agricultural 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 antimicrobials with promising activity against Mycobacterium tuberculosis, which is responsible for millions of deaths every year in the developing world, Acinetobacter baumannii, identified by the World Health Organisation as one of three “critical priority” pathogens for new antibiotic research and development, and Pythium species which cause damping off disease in germinating crops. We have also elucidated keys steps in the biosynthesis of several antimicrobials, 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 albicans and Trichomonas vaginalis). We have exploited the knowledge gained to create novel analogues of several of these metabolites, providing insights into their structure-activity relationships and producing potent derivatives that constitute a starting point for the development of new medicines and agrochemicals.

References:

  1. 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. 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.
  3. A.J. Mullins, J.A.H. Murray, M.J. Bull, M. Jenner, C. Jones, G. Webster, T.R. Connor, J. Parkhill, G.L. Challis and E. Mahenthiralingam. Genome mining identifies cepacin as a key plant-protective metabolite of the biopesticidal bacterium Burkholderia ambifaria. Nat. Microbiol. 2019, 4, 996-1005.
  4. Song, M. Jenner, J. Masschelein, C. Jones, M. Bull, S. Harris, R. Hartkoorn, A. Vocat, I. Romero-Canelón, P. Coupland, Paul, G. Webster, M. Dunn, R. Weiser, C. Paisey, S. Cole, J. Parkhill, E. Mahenthiralingam and G.L. Challis. Discovery and biosynthesis of gladiolin: a Burkholderia gladioli antibiotic with promising activity against Mycobacterium tuberculosis. J. Am. Chem. Soc. 2017, 139, 7974-7981.

BBSRC Strategic Research Priority: Sustainable Agriculture and Food: Plant and Crop Science. Renewable Resources and Clean Growth: Industrial Biotechnology. Understanding the Rules of Life: Microbiology & Structural Biology. Integrated Understanding of Health: Pharmaceuticals

    Techniques that will be undertaken during the project:

    • Recombinant protein overproduction and purification
    • Genetic manipulation
    • Antimicrobial activity assays, including MIC determination
    • Bioinformatics
    • 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
    • Organic synthesis

    Contact: Professor Greg Challis, University of Warwick