Grant: Operating Grant

Pseudomonas aeruginosa is a bacterium that causes severe and often lethal infections in humans debilitated as a result of disease, burns, surgery or severe injury. The organism is innately resistant to many antibiotics and often develops what might be termed high-level antibiotic resistance during antibiotic therapy, both of which complicate effective treatment of P. aeruginosa infections. Primary contributors to this innate and acquired antibiotic resistance are pumps within the bacterial cells that extrude antibiotics before they reach levels sufficient to kill the bacterium. Despite their contributions to antibiotic resistance, however, these pumps have other than antibiotic export as their intended function (antibiotic extrusion being a fortuitous and poorly understood 'benefit' of their operation in these bacteria) and are naturally produced in response to a variety of environmental conditions, some of which occur within the human body. Thus, invading P. aeruginosa causing infections may be expressing these efflux systems and, so, be less susceptible to antibiotic therapy. The focus of this proposal, then, is the detailed characterization of these pumps, including the identification of the specific conditions in the human body that activate antibiotic pump production in P. aeruginosa. Insights gained from this study should assist efforts to overcome resistance in treating P. aeruginosa infections.