Protonophoric effects of antimalarial drugs and alkylamines in Escherichia coli membranes

Inside-out vesicles of Escherichia coli whose lumen was acidified by substrate oxidation, were used to study the mode of pH gradient dissipation by quinoline-containing antimalarial drugs and alkylamines. The pH was dissipated by micromolar drug concentrations, the dibasic chloroquine being most potent, followed by the monobasic mefloquine, quinine and the dibasic 7H-quinoline. The time dependence of pH dissipation as a function of membrane potential suggests that the monoprotonated forms of the drugs are able to cross the bacterial membrane. Alkylamines were able to dissipate the pH gradient in the 0.01-5 mM range, their rank order of potency being related to their hydrobicity. Tertiary amines were less effective than less hydrophobic primary primary amines, implying an effect of molecular volume of their diffusion across the membrane. Both sets of results suggest that amphiphilic weak bases can cross membranes in their free-base form, become protonated in an acid environment and diffuse in this form along their concentration gradient and aided by the membrane potential, thereby dissipating the pH gradient.