Pyrrolo[2,1-c][1,4]benzodiazepine (PBD) compounds as inhibitors of quorum sensing and biofilm formation

Abstract

With the rise in antibiotic resistance, quorum sensing inhibition has emerged as a possible alternative to classical antibiotic therapy. Quorum sensing is density-dependent communication between bacteria that allows the bacteria to coordinate gene expression. This communication is accomplished through the secretion of certain signal molecules, and is often responsible for the development of pathogenicity in bacteria. By inhibiting this communication, bacteria may be prevented from expressing pathogenic traits, such as biofilm formation. In this study, 12 novel Pyrrolo[2,1-c][1,4]benzodiazepine (PBD) compounds were tested for their ability to inhibit quorum sensing using disk diffusion assays. Blank disks were loaded with the PBD compounds and overlaid with molten agar inoculated with Chromobacterium violaceum. C. violaceum is a quorum sensing indicator species. The bacteria produce a purple pigment when they undergo quorum sensing but turn white when quorum sensing is inhibited. Compounds that showed quorum sensing inhibition were then tested for the inhibition of biofilm formation. Of the 12 PBD compounds, three were determined to be QSIs. We further tested two of these, compounds 17 and 33, for their ability to inhibit biofilm formation at different concentrations. Using spectrophotometry, where a lower absorbance indicated greater quorum sensing inhibition, these compounds were also identified as biofilm inhibitors in C. violaceum. Further testing is needed to determine whether the inhibition of biofilms observed is due to quorum sensing inhibition or growth inhibition. If the inhibition of biofilms is due to inhibition of quorum sensing, future studies may determine the mechanism of inhibition.