UNIVERSITY OF CHICAGO, THE
Perhaps the greatest current challenge in the treatment of microbial infection is the development of new classes of antibiotics to combat the ever-increasing number of resistant pathogens. However, there are select bacteria that, due to their intracellular lifestyle, have always been recalcitrant to antimicrobial chemotherapy. The gram-negative zoonotic bacterium, Brucella abortus is one such pathogen. If left untreated, individuals infected with Brucella spp. develop an incapacitating chronic infection affecting multiple organ systems. We are taking an innovative approach to the study of Brucella virulence and the development of new antimicrobial compounds for the treatment of brucellosis. This work centers on the study of two protein complexes that have been implicated in the bacterial stress response in related species. The first of these protein complexes, the toxin-antitoxin (TA) system RelE-RelB, is broadly conserved in multiple pathogens. Notably, our group and others have shown that genetically disrupting such TA systems in related species (by deleting the antitoxin gene) is lethal to the cell. Thus, we predict that pharmacological disruption of protein-protein interactions in the B. abortus RelB-RelE complex will release free RelE toxin into the cytoplasm and kill the cell. This approach to killing B. abortus is independent of the cellular function of RelB-RelE. It requires only that the cell expresses these proteins. Given the broad conservation of this family of toxin-antitoxin proteins, our approach has the potential to produce new broad-spectrum antibiotics. The second protein complex on which we will focus is the PhyR/NepR antisigma system. The approach in targeting this system is different than the RelB-RelE toxin. Specifically, disruption of PhyR-NepR is not lethal, but rather reduces the ability of related bacterial species to adapt and survive under multiple stress conditions. Bacterial pathogens must reliably detect and adapt to changes in their environment in order to survive within their host. Disrupting the ability of pathogens to adapt to environmental stress by targeting stress response complexes is therefore a viable strategy in the treatment of bacterial infection.