? Pharmacological treatment with anti-microbial drugs enables the killing of infectious pathogens. However, most organisms also trigger a host mediated systemic inflammatory response syndrome for which there is no effective treatment. In the case of shigellosis, the inflammatory response syndrome is localized primarily to the gut. The injury caused can be severe and life threatening. Our pharmacological aim is to make a dendrimer aminosaccharide as a new drug that will antagonize lipopolysaccharide - Toll Like Receptor- (TLR-) 4 cell surface mediated proinflammatory responses without affecting other Toll Like Receptor mediated responses. This new drug will enable the effective combination of existing antimicrobial drug therapy with a new immuno-modulatory drug to substantially improve the treatment of severe shigellosis. Pharmaceutical and immuno-modulatory therapies will therefore be combined. We will design, develop and optimize a major new therapeutic approach for treating a life threatening pathogen of global importance that has also been classified as a bioterror agent. In addition, many other Gram-negative bacteria can also trigger a systemic inflammatory response syndrome after the binding of bacterial LPS to patient cell surface TLR-4. This leads to the release of cytokines that cause severe tissue injury, shock and death. Therefore, the potential therapeutic applicability of a dendrimer aminosaccharide with the properties that we describe could be much broader that just the treatment of shigellosis. ? ?
? In shigellosis, the patient's inflammatory response syndrome causes life threatening damage to the gut. Our pharmacological aim is to make a dendrimer aminosaccharide to prevent this damage. This new drug will enable the effective combination of existing antimicrobial drug therapy with a new immuno-modulatory drug to substantially improve the treatment of this infection of global importance. ? ? ?
