Carbonylacrylic Derivatives and Their Ability to Disrupt Biofilm Formation

Abstract

The rapid emergence of bacterial resistance to antibiotics has greatly pressed the need for novel therapeutics. One of the strategies bacteria use to enhance their resistance toward antibiotics is to embed themselves into polymeric matrices known as a biofilm. Bacteria in a biofilm state are highly resistant towards antibiotics and immune response, thereby more difficult to eradicate. Hence, antibiofilm agents are considered an alternative strategy to unravel problems regarding bacterial antibiotic resistance. Our lab has focused on bacterial communication process called quorum sensing (QS), which is crucial for bacteria to conduct group behaviors such as biofilm. Cysteine residue of LasR, key QS protein regulator, has been suggested to play an important role in QS-mediated biofilm formation. In addition, cysteine-containing biomolecules have been implicated in bacterial pathogenesis. Herein, we explored the ability of thiol-reactive molecules for their ability to interfere with biofilm formation in pathogenic Gram-negative Pseudomonas aeruginosa (P. aeruginosa). We hypothesized that the thiol-reactive molecules could potentially react with sulfhydryl group of cysteine residue of crucial QS enzyme or of cysteine-containing biomolecules that may lead to the reduce in the ability of the pathogen to form biofilm. Carbonylacrylic compounds were previously reported to rapidly undergo thiol-Michael reaction with cysteine-containing proteins under physiological conditions. Total of three new carbonylacrylic derivatives were synthesized and tested for their anti-biofilm activity. All synthesized compounds could inhibit biofilm formation in a concentration-dependent manner without toxicity to bacteria. Derivative 1a exhibited the most potent antibiofilm activity with IC50 of 85 µM.