The influence of electric charge of aromatic heptaene macrolide antibiotics on their activity on biological and lipidic model membranes.

Natural aromatic heptaene macrolide antibiotics and their N-acyl and methyl ester derivatives, which differ mainly in their electric net charge, were compared for their efficiency in inducing yeast growth inhibition, red blood cell lysis, and increase in the ionic permeability of large unilamellar lipidic vesicles. Antifungal activity was found to decrease in the following order: neutral congruent to positively charged greater than negatively charged compounds. Hemolytic activity decreased in the order: neutral greater than negatively charged much greater than positively charged compounds. On lipidic model membranes, themselves either positively or negatively charged, electrostatic interaction was shown to have practically no influence on the efficiency of the differently charged antibiotics. On both biological and model systems, positively charged antibiotics consistently were found to be more active on ergosterol-containing than on cholesterol-containing membranes, and were therefore considered as potentially good candidates for specific antifungal agents.