Biochemical characterization of a Pseudomonas aeruginosa phospholipase D

Abstract

Phospholipase D (PLD) is a ubiquitous enzyme found in prokaryotic and eukaryotic organisms that generates phosphatidic acid. A number of human bacterial pathogens produce PLD as virulence factors to promote infections. PldA of P. aeruginosa is one such example and not only modulates host cell signaling to promote cell invasion, but also mediates bacterial killing by perturbing cell wall stability. Both of these processes may directly and indirectly contribute to host colonization by P. aeruginosa. Despite the recognized significant of these bacterial PLD, little progress has been made toward understand their enzymatic activity in vitro or upon interaction with host cells. Here, the catalytic properties of PldA were characterized providing insights into possible molecular mechanisms by which PldA promotes cell invasion. Occurrences of multi-drug resistant bacterial infections are on the rise, however limited novel bactericidal agents are in development. Inhibition of virulence mechanisms is an emerging strategy to identify novel therapeutic targets for antibacterial therapy development. Presented here is a description of the first small-molecule inhibitor of a PLD virulence factor, a necessary preliminary step to confirm PldA inhibition as an efficacious strategy to treating P. aeruginosa infections.