Carbonylacrylic Derivatives and Their Ability to Disrupt Biofi lm 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 biofi lm. Bacteria in a biofi lm state are highly resistant towards antibiotics and immune response, thereby more diffi cult to eradicate. Hence, antibiofi lm 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 biofi lm. Cysteine residue of LasR, key QS protein regulator, has been suggested to play an important role in QS-mediated biofi lm 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 biofi lm 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 biofi lm. 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-biofi lm activity. All synthesized compounds could inhibit biofi lm formation in a concentration-dependent manner without toxicity to bacteria. Derivative 1a exhibited the most potent antibiofi lm activity with IC50 of 85 μM.