Thioridazine RXDX-106 has diverse effects on gene expression as demonstrated in this study; however, the question of how these effects arose remains to be answered. Thioridazine is known to intercalate the membrane close to the polar/apolar

interface in the lipid bilayer (Hendrich et al., 2002) as well as between nucleic bases of DNA, resulting in the inhibition of all DNA-based processes (Stolze & Mason, 1991; Martins et al., 2004). Furthermore, thioridazine induces ultrastructural changes in MRSA such as affecting the structure of the cell envelope, resulting in bacterial lysis at clinically relevant concentrations (Martins et al., 2004). The impact of thioridazine on gene expression in M. tuberculosis has previously been analyzed using whole genome DNA microarrays. The expression of genes encoding membrane proteins, efflux pumps, oxidoreductases, and enzymes involved in fatty acid metabolism and aerobic respiration were affected in this study (Dutta et al., 2010). A recent study with epicatechin gallate in S. aureus, which has a similar effect on resistance shows that the compound binds predominantly to the cytoplasmic membrane. It decreases the fluidity of the bilayer and induces the expression of genes belonging to the general cell wall stress stimulon, including the vraSR two-component system (Bernal et al.,

2010). We therefore speculate that thioridazine, in a similar manner, affects the membrane fluidity of S. aureus, leading to protein mislocation, misfolding, or changed protein activity. BMS-777607 order This is likely to disturb the signal transduction across the membrane in response to inhibition of cell wall synthesis by oxacillin, and could explain the changes in the expression levels of genes involved in cell wall biosynthesis observed here and in our previous study (Klitgaard et al., 2008). The results presented

in this study give important indications of the mechanism behind the reversal of resistance in MRSA by thioridazine. We believe that studies concerning the effect of Regorafenib thioridazine on the cytoplasmic membrane of S. aureus as well as the effect of the combinatorial treatment on global gene expression will contribute further to the full understanding of the mechanism. Additionally, it will be important to investigate the extent of the mechanism on a selection of clinical MRSA isolates and the impact on clinical treatment opportunities these observations may have. This work was supported by The Lundbeck Foundation (grant number R32-A2819 to B.H.K.) and The Novo Nordisk Foundation (J.K.K.). “
“Survival in acidic environments is important for successful infection of gastrointestinal pathogens. Many bacteria have evolved elaborate mechanisms by inducing or repressing gene expression, which subsequently provide pH homeostasis and enable acid survival. In this study, we employed comparative proteomic analysis to identify the acid-responsive proteins of a food-borne enteric bacterium, Yersinia pseudotuberculosis.