Abstract: Methods are provided relating to the enhanced cytoplasmic accumulation of amphipathic weakly basic or amphipathic cationic molecules in prokaryotes and eukaryotes under conditions of high extracellular pH. Furthermore, the methods relate to the unexpected synergistic effects of high extracellular pH and disrupted cellular efflux mechanisms on the cytoplasmic accumulation of amphipathic weakly basic or amphipathic cationic molecules in prokaryotes and eukaryotes. Methods are also provided for increasing the therapeutic potency of amphipathic weakly basic or amphipathic cationic compounds, e.g. antiseptics and disinfectants by using the antiseptic or disinfectant in the presence of a multiple drug resistance inhibitor such as reserpine. Finally, methods also relate to the exploitation of the aforementioned discoveries in the screening of small molecules, and libraries thereof, for biological activity in prokaryotes and eukaryotes.

Abstract: Methods are provided relating to the enhanced cytoplasmic accumulation of amphipathic weakly basic or amphipathic cationic molecules in prokaryotes and eukaryotes under conditions of high extracellular pH. Furthermore, the methods relate to the unexpected synergistic effects of high extracellular pH and disrupted cellular efflux mechanisms on the cytoplasmic accumulation of amphipathic weakly basic or amphipathic cationic molecules in prokaryotes and eukaryotes. Methods are also provided for increasing the therapeutic potency of amphipathic weakly basic or amphipathic cationic compounds, e.g. antiseptics and disinfectants by using the antiseptic or disinfectant in the presence of a multiple drug resistance inhibitor such as reserpine. Finally, methods also relate to the exploitation of the aforementioned discoveries in the screening of small molecules, and libraries thereof, for biological activity in prokaryotes and eukaryotes.