Discovery, biosynthesis and bioengineering of antibiotics from Gram-negative bacteria
Abstract
The overwhelming majority of antibiotics in clinical use are natural products or semi-synthetic derivatives produced by soil bacteria and filamentous fungi. Pathogenic microorganisms are becoming increasingly resistant to these compounds, and there is an urgent need to discover novel antibiotics to address the emerging health threat this poses. In this lecture, the discovery and biosynthetic elucidation of antibiotic natural products from underexplored Gram-negative bacterial genera will be discussed, 1, 2 and the development of bioengineering approaches for the production of novel analogues with enhanced activity will be described. In particular, the focus will be on polyketide antibiotics with potent activity against important antibiotic-resistant pathogens such as Mycobacterium tuberculosis and Acinetobacter baumannii.
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. 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, DOI: 10.1038/NCHEMBIO.2549
Abstract
The overwhelming majority of antibiotics in clinical use are natural products or semi-synthetic derivatives produced by soil bacteria and filamentous fungi. Pathogenic microorganisms are becoming increasingly resistant to these compounds, and there is an urgent need to discover novel antibiotics to address the emerging health threat this poses. In this lecture, the discovery and biosynthetic elucidation of antibiotic natural products from underexplored Gram-negative bacterial genera will be discussed, 1, 2 and the development of bioengineering approaches for the production of novel analogues with enhanced activity will be described. In particular, the focus will be on polyketide antibiotics with potent activity against important antibiotic-resistant pathogens such as Mycobacterium tuberculosis and Acinetobacter baumannii.
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. 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, DOI: 10.1038/NCHEMBIO.2549
