Phenazine Scaffolds as a Potential Allosteric Inhibitor of LasR Protein in Pseudomonas aeruginosa.

Abstract

Millions of individuals suffer from chronic infections caused by bacterial biofilms, resulting in significant loss of life. Pseudomonas aeruginosa stands out as a major culprit in causing such chronic infections, largely due to its antibiotic resistance. This pathogen poses a considerable threat in healthcare settings, particularly to critically ill and immunocompromised patients. The persistence of chronic and recurrent bacterial infections is often attributed to bacterial biofilms. Therefore, there is an urgent need to discover novel small molecules capable of efficiently eliminating biofilms independent of bacterial growth. In this project, an in silico drug discovery approach was employed to identify nine halogenated-phenazine compounds as allosteric inhibitors of the LasR protein. The LasR is a key transcription factor that triggers other quorum-sensing systems and plays a crucial role in biofilm formation and activation of virulence genes. By inhibiting LasR, specifically targeting its allosteric site, the dimerization of LasR and subsequent biofilm formation could be prevented. Molecular docking and simulations, coupled with binding energy calculations, identified five compounds with potential as anti-biofilm agents. These compounds exhibited higher binding affinities to the distal site, suggesting their structural capability to interact with allosteric site residues of the LasR protein. Based on these findings, it is proposed that these compounds could serve as promising leads for the treatment of biofilm and quorum-sensing-related infections.