Pseudomonas aeruginosa is a ubiquitous Gram-negative pathogen and a prominent cause of chronic infections in patients with cystic fibrosis. Under the control of quorum sensing it adapts to the microaerobic and nutrient-deplete conditions in the lung by directing carbon flux through an anaplerotic pathway called the glyoxylate shunt. The glyoxylate shunt enables growth on acetate, in the form of Acetyl-CoA, derived from oxidation of fatty acids. Normally this carbon would be lost in the tricarboxylic acid cycle as CO2 , meaning that acetate may be used to generate energy but not biomass. The shunt bypasses these decarboxylative steps to provide a route from isocitrate to gluconeogenic precursors, thereby facilitating both anabolism and gluconeogenesis. It is known that inactivation of the glyoxylate shunt renders P. aeruginosa avirulent in a murine burn model; the correct functioning of the shunt is necessary for fitness and virulence. It is therefore a promising target for the study and treatment of chronic infections. Metabolic regulation of the glyoxylate shunt deviates significantly from the better understood E. coli model. Our group is studying the enzymology of the TCA/shunt branch point in P. aeruginosa using a combination of techniques. We describe our study of the structure and function of isocitrate lyase and malate synthase, the discovery of small molecules that inhibit them, and their evaluation as antibacterial agents. We also describe the development of new methodology for the synthesis of these leads.

Glyoxylate shunt as an antibacterial drug target

253rd National Meeting (2017)

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