Bacterial biofilm infections have emerged as a serious threat to human health. The biofilm is a major virulence factor contributing to bacterial invasiveness and persistence causing acute and chronic infections.1 Biofilm encased bacteria can withstand sterilisation, allowing them to reside on hospital equipment, such as ventilators, exposing immunocompromised patients to multi-drug resistant bacteria. Pseudomonas aeruginosa is of major concern for ventilator related pneumonia, particularly in cystic fibrosis patients.2 With limited treatment options available for drug resistant bacterial pathogens, the development of lead molecules with activity against novel biological targets is crucial.
The key signaling molecule responsible for biofilm formation is cyclic dimeric guanosine monophosphate (cyclic di-GMP), which is naturally synthesised from two guanosine molecules.3 Intracellular cyclic di-GMP concentrations can be reduced via catalytic hydrolysis or product feedback inhibition to prevent further molecule formation.4 This research examined the design of cyclic di-GMP analogues as antivirulence agents that inhibit biofilm formation.
Modifications were made to the structure of cyclic di-GMP to improve synthetic accessibility and bioavailability, including modifying the nucleoside and replacing the negatively charged phosphodiester with neutral bioisosteres. Ligand design was guided by computational analysis, which compared the interactions of each compound with the binding modes of the natural precursor to select the most promising compounds for synthesis. Biological assessment of the compound was conducted via P. aeruginosa biofilm inhibition and eradication assays. The results of which, will be presented at the conference.