Prof. Martin Welch
Dept. Biochemistry, Cambridge University, UK
“2C or not 2C”… Central metabolism as an anti-bacterial drug target
Pseudomonas aeruginosa is designated by the WHO as a “priority pathogen”. The reasons for this dubious accolade are clear; the organism is ubiquitous in the built environment, manifests an unparalleled ability to form drug-resistant biofilms, and exhibits a truly frightening ability to degrade soft tissue. To make matters worse, P. aeruginosa has a remarkable propensity to acquire resistance against almost all classes of antibiotic, making infections extremely difficult to resolve. We therefore need to develop new interventions to manage such infections.
In spite of all this doom-and-gloom, the organism is not inherently “malevolent”… it secretes tissue-degrading virulence factors for one reason, and one reason alone; to acquire nutrient. And since nutrient acquisition is hardwired into central metabolism, it should come as no surprise that virulence is tightly-regulated by flux through certain metabolic “nodes”. Furthermore, it turns out that P. aeruginosa has radically different dietary preferences compared with say, E. coli. P. aeruginosa is a carnivore, whereas E. coli prefers the dessert menu. Targeting central metabolism for drug development therefore offers the promise of delivering a powerful double whammy to the organism, by preventing growth and by dampening virulence.
In this talk, we’ll look at how an understanding of the pathogen’s metabolic peccadillos – and of the infection site nutritional environment - can allow us to develop more effective therapeutic interventions. By way-of-example, we take a deep dive into fatty acid catabolism (P. aeruginosa loves fatty acids…) and show how (and why) some of these pathways can be exploited as drug targets. Finally, we’ll take a stroll through some fragment-based drug design (targeting the enzyme methylcitrate synthase – I’ll explain why this enzyme is so important in the talk) and touch on how mutagenesis screens can facilitate drug re-purposing.
Selected references
1. Pseudomonas aeruginosa acyl-CoA dehydrogenases and structure-guided inversion of their substrate specificity. Meng Wang, Prasanthi Medarametla, Thales Kronenberger, Tomas Deingruber, Paul Brear, Wendy Figueroa, Pok-Man Ho, Thomas Krueger, James C. Pearce, Antti Poso, James G. Wakefield, David R. Spring, and Martin Welch. Nature Communications 16, 2334 (2025). https://doi.org/10.1038/s41467-025-57532-z
2. The 2-methylcitrate cycle and the glyoxylate shunt in Pseudomonas aeruginosa are linked through enzymatic redundancy. Andre J. Wijaya, Stephen K. Dolan, Michael Kohlstedt, Lars Gläser, Paul Brear, Stephen Geddis, Christoph Wittmann, David R. Spring, and Martin Welch. Journal of Biological Chemistry (2025). https://doi.org/10.1016/j.jbc.2025.108355
3. Why antibiotics sometimes fail to clear infections: contribution of the infection ecosystem and biogeography. Rahan Rudland Nazeer, Isabel Askenasy, Jemima E. V. Swain, Martin Welch. NPJ AMAR (2024) 10.1038/s44259-024-00063-2
4. Systems-wide dissection of organic acid assimilation in Pseudomonas aeruginosa reveals a novel path to underground metabolism. SK Dolan, AJ Wijaya, M Kohlstedt, L Glaser, P Brear, R Silva-Rocha, C Wittmann and M Welch. mBio (2022). https://doi.org/10.1128/mbio.02541-22
5. Contextual flexibility in Pseudomonas aeruginosa central carbon metabolism during growth in single carbon sources. Stephen K. Dolan, Michael Kohlstedt, Stephen Trigg, Pedro Vallejo Ramirez, Christoph Wittmann, Clemens F. Kaminski, and Martin Welch. mBio 2020 Mar 17;11(2):e02684-19. https://doi.org/10.1128/mBio.02684-19
6. Audrey Crousilles, Stephen K. Dolan, Paul Brear, Dimitri Y. Chirgadze and Martin Welch. Gluconeogenic precursor availability regulates flux through the glyoxylate shunt in Pseudomonas aeruginosa. Journal of Biological Chemistry. 293: 14260-14269 (2018)
7. Alyssa C. McVey, Prasanthi Medarametla, Xavier Chee, Sean Bartlett, Antti Poso, David R. Spring, Taufiq Rahman and Martin Welch. Structural and Functional Characterization of Malate Synthase G from Opportunistic Pathogen Pseudomonas aeruginosa. Biochemistry. 56: 5539-5549. (2017)