Wednesday, 3 April 2024 4:00pm – 5:00pm

This seminar will be delivered in Lecture Theatre 4

Speaker: Professor Greg Challis

Host: Dr Constance Bailey

Title: Discovery, biosynthesis, and evolution of natural products in the opportunistic human pathogen Burkholderia gladioli

Abstract: Many structurally complex, biologically active natural products have been isolated from soil dwelling Gram-positive Actinobacteria. In contrast, the potential of Gram-negative bacteria to produce natural products has been relatively underexplored. In this lecture I will discuss our recent efforts to investigate the production of antibiotics and other bioactive metabolites by the Gram-negative opportunistic human pathogen Burkolderia gladioli. These have led to the discovery of novel polyketides with potent activity against important antibiotic-resistant pathogens such as Mycobacterium tuberculosis and Candida albicans, and human cancer cell lines.^1,2 The gene clusters responsible for the biosynthesis of these metabolites have been identified and extensive ongoing efforts to elucidate the biosynthetic pathways they encode will be described.^2-5 Recent insights from intra-species genome comparisons into mechanisms of biosynthetic assembly line evolution will also be discussed, signposting promising new synthetic biology strategies for the creation of novel natural product analogues.

1. L. 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.
2. I.T. Nakou, M. Jenner, Y. Dashti, I. Romero-Canelón, J. Masschelein, E. Mahenthiralingam and G.L. Challis. Genomics-driven discovery of a novel glutarimide antibiotic from Burkholderia gladioli reveals an unusual polyketide synthase chain release mechanism. Angew. Chem. Int. Ed. 2020, 59, 23145-23153.
3. M. Jenner, S. Kosol , D. Griffiths, P. Prasongpholchai, L. Manzi, A.S. Barrow, J.E. Moses, N.J. Oldham, J.R. Lewandowski  and G.L. Challis. Mechanism of intersubunit ketosynthase–dehydratase interaction in polyketide synthases. Nat. Chem. Biol. 2018, 14, 270-275.
4. C. Hobson, M. Jenner, X. Jian, D. Griffiths, D.M. Roberts, M. Rey and G.L. Challis. Diene incorporation by a dehydratase domain variant in modular polyketide synthases. Nat. Chem. Biol. 2022, 18, 1410-1416.
5. X. Jian, F. Pang, C. Hobson, M. Jenner, L.M. Alkhalaf and G.L. Challis. Antibiotic skeletal diversification via differential enoylreductase recruitment and module iteration in trans-acyltransferase polyketide synthases. J. Am. Chem. Soc. 2024, 146, 6114-6124

Bio: Greg Challis completed a DPhil in Organic Chemistry at the University of Oxford under the supervision of Prof Sir Jack Baldwin in 1998. Following postdoctoral research in the Department of Chemistry at Johns Hopkins University and the Department of Genetics at the John Innes Centre, he was appointed in 2001 as Lecturer in Chemical Biology in the Department of Chemistry at the University of Warwick. In 2006, he was promoted to Professor and in 2016 he was appointed the Monash-Warwick Alliance Professor of Sustainable Chemistry (Chemical and Synthetic Biology). In 2021, he joined the ARC Centre of Excellence for Innovations in Peptide and Protein Science as a Chief Investigator. Greg’s research interests encompass the discovery, mechanism of action, biosynthesis and bioengineering of bioactive natural products.