DNA Minor Groove-binding Drugs and Food-borne Pathogens

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DESCRIPTION (provided by applicant): Dispersion of biological warfare agents has the potential of causing significant morbidity and mortality, and public panic. Thus, further investigation into the treatment and prevention of the detrimental consequences of biological warfare is imperative. The focus of this proposal is food-borne pathogens, particularly category B bacterial pathogens of the Salmonella species and Escherichia coli, and their toxins. Compared with other biological infectious agents, these organisms require less expertise to handle, and by contaminating food products, they have the potential to produce disease outbreaks in large groups of people and over broad geographic regions. These organisms have the potential to spread from the gastrointestinal tract into the blood stream, resulting in bacteremia and endotoxemia, which has devastating consequences in patients. Over the past several years we have been interested in the pathophysiology of endotoxin from Salmonella typhi and Escherichia coli. In recent investigations, we have preliminary data to suggest a naturally occurring compound, distamycin A, may improve outcome in a mouse model of endotoxemia. Distamycin A is known to bind to the minor groove of DNA in AT-rich regions, and its effect occurs in part by disrupting the binding of transcription factors to DNA such as nuclear factor (NF)-kappa B and interferon regulatory factors (IRFs). Our overall hypothesis is that DNA minor groove-binding drugs will suppress the expression of genes that play a critical role in the regulation of inflammation and vascular tone during an endotoxin response, and thus provide a novel therapeutic option for toxins of food-borne pathogens. Thus, the goals of this proposal are: 1) to determine whether drugs that bind to AT-rich regions of the minor groove of DNA improve outcome in mice exposed to endotoxin of the food-borne pathogens, Salmonella typhi and Escherichia coli, 2) to identify specific genes, regulated by DNA minor groove-binding drugs, that contribute to an improved response during endotoxin exposure, and 3) to characterize the mechanisms by which DNA minor groove-binding drugs alter gene expression leading to improved outcome during endotoxin exposure.