Bacterial resistance to antibiotics is a significant global public health issue, with the Centers for Disease Control and Prevention reporting that 2 million Americans become infected with antibiotic-resistance diseases each year. One such bacterial strain, Pseudomonas aeruginosa, infects immunocompromised patients and those with cystic fibrosis. These bacterial cells rely on a quorum sensing communication system.
Recently, scientists at the Helmholtz Institute for Pharmaceutical Research Saarland in Germany conducted an experiment using surface plasmon resonance (SPR) to characterize the binding properties of compounds in this communication system. By identifying novel compounds that disrupt quorum sensing communication, scientists may be able to treat P. aeruginosa-related diseases.
Surface Plasmon Resonance Detects Compound Binding Properties
The bacterial quorum sensing system releases small signalling molecules. These molecules tell the cell to turn on genes responsible for virulence and the creation of biofilms. The researchers discovered a new class of compounds called PqsD inhibitors, which may disrupt this cellular signalling. These PqsD inhibitors have a catechol moiety connected to an ester moiety. How these structures interact with PqsD to inhibit its activity was investigated using SPR.
Scientists conducted two experiments to investigate binding properties of the PqsD inhibitor compounds. The first characterized binding between untreated PqsD and the putative inhibitors. The second experiment used PqsD that was pre-treated with ACoA, one of the targets of PqsD’s enzymatic activity. Comparing the association and dissociation curves of the SPR data allowed the scientists to determine whether the novel compounds compete with ACoA when binding to the active site of PqsD.
The SPR experiments employed a Reichert SR7500 DC instrument with optical biosensor. The researchers used Scrubber software to process and analyze the data. The results showed that the association and dissociation curves were similar with untreated PqsD and PqsD treated with ACoA. Thus, the novel inhibitory compounds do not compete with ACoA when they bind to PqsD.
These findings suggest that the PqsD inhibitors behave like channel blockers. They likely interact with the upper portion of the substrate channel, blocking the ability of ACoA to reach the active site.
Impact of SPR Findings on Antibiotic Resistant Bacteria
Using Reichert’s SPR technology is the strongest available method of characterizing the binding properties of novel PqsD inhibitors. By disrupting the bacteria’s quorum sensing system, PqsD inhibitors can disrupt P. aeruginosa’s ability to communicate and create biofilms. Thus, it may be a potential treatment for antibiotic resistant bacterial infection.
For more information on this topic, you can read the paper: “Catechol-based substrates of chalcone synthase as a scaffold for novel inhibitors of PqsD," by Allegretta, G., Weidel, E., Empting, M., Hartmann, R.W., (2015) European Journal of Medicinal Chemistry, 90, pp.351-359.