(135c) Invited Speaker: Anti-Toxin Strategies As an Antibiotic Alternative

Pathogenic bacteria produce numerous virulence factors, including protein toxins, to enhance their growth and survival within the host. Our lab seeks to understand the mechanisms of bacterial toxin delivery to identify and exploit therapeutic targets. In recent years, we have focused on a leukotoxin (LtxA) secreted by A. actinomycetemcomitans, which specifically kills human white blood cells to disrupt the host immune response and therefore plays a key role in bacterial colonization of the host. Disruption of the mechanism of action of this toxin would eliminate this immunosuppressive function, thus rendering the bacteria susceptible to natural clearance mechanisms. The cell type specificity of LtxA arises from its reported targeting of the lymphocyte function-associated antigen-1 (LFA-1) integrin, which is only expressed by human white blood cells. In addition, we recently showed that LtxA binds with a strong affinity to cholesterol, and inhibition of this binding to cholesterol prevents LtxA-mediated cytotoxicity. Using our knowledge of these essential membrane interactions, we have designed several targeted inhibitors of LtxA binding to host cells. In addition, we have uncovered the mechanism of toxin inhibition by catechins, a class of polyphenolic compounds found in tea. Together, these projects demonstrate the potential of using mechanistic information about toxin membrane interactions to design anti-toxin strategies to treat bacterial associated diseases.