Research spotlight: Small molecule inhibitors of bacterial choline catabolism

By Matt Wargo • November 23rd, 2011

Citation: Fitzsimmons, L.F., Flemer, S. Jr, Wurthmann, A.S., Deker, P.B., Sarkar, I.N., Wargo, M.J. 2011. Small-Molecule Inhibition of Choline Catabolism in Pseudomonas aeruginosa and Other Aerobic Choline-Catabolizing Bacteria. Appl Environ Microbiol. 77(13):4383-4389.

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Authors Associated with MMG:
Liam F. Fitzsimmons – is a Research Technician in MMG
I. Neil Sarkar – is an Assistant Professor in MMG
Matthew J. Wargo – is an Assistant Professor in MMG

Summary:
The authors sought to generate choline analogues to study bacterial choline catabolism in vitro and in situ. Here they report the characterization of a choline analogue, propargylcholine, which inhibits choline catabolism at the level of dimethylglycine demethylation in Pseudomonas aeruginosa. Using genetic analyses and 13C nuclear magnetic resonance they demonstrate that propargylcholine is catabolized to its inhibitory form, propargylmethylglycine, a conclusion supported by the function of chemically synthesized propargylmethylglycine. Because the enzyme targeted by propargylmethylglycine has homologues in many bacteria, the authors examined the broader utility of propargylcholine and propargylmethylglycine by assessing growth of other members of the proteobacteria that are known to grow on choline and possess putative DgcA homologues. While propargylcholine only inhibited growth in P. aeruginosa, propargylmethylglycine was able to inhibit choline-dependent growth in all tested proteobacteria, including Pseudomonas mendocina, Pseudomonas fluorescens, Pseudomonas putida, Burkholderia cepacia, Burkholderia ambifaria, and Sinorhizobium meliloti.

Impact and Significance:
Choline is abundant in association with eukaryotes and plays roles in osmoprotection, thermoprotection, and membrane biosynthesis in many bacteria. Likewise, aerobic catabolism of choline is widespread among soil proteobacteria, particularly those associated with eukaryotes. Catabolism of choline as a carbon, nitrogen, and/or energy source may play important roles in association with eukaryotes, including pathogenesis, symbioses, and nutrient cycling. To generate a set of tools to study choline catabolism in vitro and in situ, the authors synthesized a set of inhibitory molecules that targeted a specific step in the choline catabolic pathway. These compounds affected P. aeruginosa virulence-related phenotypes and propargylmethylglycine prevented growth on choline in a variety of proteobacteria. Thus the authors conclude that chemical inhibitors of choline catabolism will be useful for studying this pathway in clinical and environmental isolates and could be a useful tool to study proteobacterial choline catabolism in situ.

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