Determination of the Cellular Effects of Antibiofilm Therapeutics and the Characterization of Potential Cellular Targets in Bacteria.

摘要

This work shows the cellular effects of 2-aminoimidazole derivatives with antibiofilm activity against the pathogenic bacterial species Acinetobacter baumannii and the structural and functional characterization of a biofilm regulating target, SinR, in Bacillus subtilis. Bacterial biofilms are a complex organization of phenotypic subpopulations that have shielded themselves from their local environment. In an industrial setting, biofilms are a source of costly damage and delays in production, but in hospitals, they have become a primary source of many life-threatening, multi-drug resistant infections. Yet, many species form biofilms that have beneficial uses, especially in agricultural and bioremediation. The 2-aminoimidazole agents have displayed the ability to not only inhibit biofilm formation but also to disperse established biofilms across a vast range of bacterial and fungal species without antimicrobial activity. In addition, some classes of these molecules have been shown to synergistically work with conventional antibiotics to resensitize previously drug-resistant pathogens (Rogers, 2010; Harris, 2012). One class of these antibiofilm compounds, the reverse-amides, can penetrate the membrane barriers of A. baumannii and target the biofilm regulator, BfmR, a two-domain response regulator. The full-length solution structure of SinR has also been solved via nuclear magnetic resonance spectroscopy or NMR, and using combination of structural and interaction data, it was evident that SinI destabilizes the SinR active state by replacing key residues in the tetrameric interface, drastically reducing SinR's ability to bind and contort its DNA targets.