Chemical Probes of Complement Pathways

Project Summary/Abstract Section The rise of resistant strains of antibiotic-resistant bacterial pathogens demands new approaches to combat the infectious diseases they cause. An alternative to standard small-molecule antibiotics is to co-opt endogenous mechanisms for eliminating microbes, such that they operate rapidly and efficiently to eliminate the infectious cells. Complement recruitment offers a means of co-opting these natural defenses, but implementing this approach requires insight into the molecular mechanisms underlying complement-induced immune responses. The focus of Aim 1 is to generate a series of multifunctional compounds that bind to the gram-negative bacteria Pseudomonas aeruginosa through different mechanisms. The utility of these compounds to effect recruitment and cell killing will be assessed. These studies will provide insight into the relative efficiencies of the classical and lectin-mediated complement pathways. In Aim 2, the probes developed in Aim 1 will be evaluated for their ability to promote pathogen uptake by immune cells and the consequences on immune cell signaling. We anticipate that the pursuit of these aims will reveal insight into the utility of co-opting complement as a means of eliminating critical pathogens. Significance: The overall objective of this application is to develop new chemical probes to explore the consequences of different complement recruitment strategies. We anticipate that this knowledge will ultimately lead to the identification of new strategies for treating infections caused by gram- negative bacteria.