Thioridazine protects the mouse from a virulent infection by Salmonella enterica serovar Typhimurium 74

When administered to mice at doses of 100 mu g/mouse and 200 mu g/mouse, thioridazine (TDZ) significantly protected animals from the lethality produced by a virulent strain of Salmonella enterica serovar Typhimurium and reduced the number of bacteria retrieved from the spleen, liver and heart blood. The protection conferred by TDZ against a virulent Salmonella infection is hypothesised to be due to a reduction in the 55 kDa virulence protein of the outer membrane of the organism, as this protein is almost totally absent when the organism is exposed to the phenothiazine. It is further hypothesised that the reduction in the 55 kDa virulence factor renders the organism susceptible to the action of hydrolytic enzymes of the neutrophil phagolysosome, whereas in the absence of exposure to TDZ intracellular ingestion and localisation of the phagocytosed bacterium does not result in killing owing to rapid induction of the two-step PmrA/B regulon that results in the eventual synthesis and insertion of lipid A into the nascent lipopolysaccharide layer of the outer membrane. (C) 2009 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.