Enhancing the antibiotic susceptibility of Pseudomonas aeruginosa biofilms by quorum sensing inhibition

Abstract

Biofilm forming bacteria are industrially and medically relevant organisms that are exceptionally resistant to garden variety antimicrobial treatments. This resistance is due in part to a biofilm forming bacteria's ability to sense and communicate with neighboring bacteria. As a result of this intercellular communication, bacteria are able to cooperate as a complex community. This communication system is used to modulate important facets of biofilm behavior and thus is an attractive target for biofilm control and potential antimicrobial agents. Inhibition of the molecular signaling system used by biofilm forming bacteria could lead to an effective treatment of chronic bacterial infections by interrupting the communication that promotes biofilm formation. Specifically, this will be accomplished be preparing synthetic analogues of signaling molecules possessing the N-acyl homoserine lactone structural motif. This structural component is well conserved among the signaling molecules in biofilm forming bacteria and it is hoped that these analogues will inhibit biofilm formation in Pseudomonas aeruginosa.Synthetic analogues of the N-acyl-L-homoserine lactone structural motif have been prepared that inhibit the signaling in Pseudomonas aeruginosa. These synthetic inhibitors have also been shown, using a novel application of the colony biofilm assay, to increase the susceptibility of Pseudomonas aeruginosa biofilms to treatment with the antibiotic tobramycin. Additional inspiration has been taken from the structure of bacterial communication molecules that has lead to the design and synthesis of a novel class of biocides. These bifunctional molecules incorporate a biocidal property into the N-acyl-L-homoserine lactone structure. This bifunctionality could potentially enhance the specificity or potency of a biocide over the currently available treatments.