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Inhibition of Pseudomonas aeruginosa Virulence factor, PlcH, by Host-derived Lipids
O'Brien, Laura C
O'Brien, Laura C
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Abstract
Pseudomonas aeruginosa is a bacterial pathogen that has high prevalence in cystic fibrosis patients. An important virulence factor of this pathogen is the hemolytic phospholipase C, PlcH, that functions in the hemolysis of cell membranes. Sphingomyelin is a major sphingolipid found in cell membranes that is hydrolyzed by PlcH. Other sphingolipids that share a common backbone with sphingosine interact with PlcH as well, sometimes leading to PlcH inhibition. Sphingosine-1-phosphate (S1P) is one of these inhibitory sphingolipids, discovered in the Wargo lab to have a large inhibitory effect on PlcH. While computational models have been constructed to analyze this binding interaction, there is still a lot not understood about it. In this study, I analyze a variety of sphingolipids that share a common backbone with sphingosine and S1P. Under conditions allowing for the measurement of enzyme activity, I measured the percent inhibition occurring under varying concentrations of these lipids. In addition to this, I constructed four P. aeruginosa PlcH mutants to determine the importance of specific binding interactions. Lipids with shorter hydrocarbon tails were noted to have lower inhibition of PlcH, as well as those with phosphono-bonded phosphate heads. The four mutants had differential results, including Trp114 which is potentially an important interaction residue in PlcH to bind S1P.
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Date
2025-01-01