Serum Prevents Interactions between Antimicrobial Amphiphilic Aminoglycosides and Plasma Membranes.

Antimicrobial cationic amphiphiles have broad-spectrum activity, and microbes do not readily develop resistance to these agents, highlighting their clinical and industrial potential. Cationic amphiphiles perturb the integrity of membranes leading to cell death, and the lack of discrimination between microbial and mammalian plasma membranes is thought to be one of the main barriers of using these agents for the treatment of systemic infections. Here, we describe the synthesis and study of 20 antimicrobial cationic amphiphiles that are derivatives of the aminoglycoside nebramine with different numbers of alkyl chain ethers that differ in length and degree of unsaturation. We determined antifungal activities and evaluated hemoglobin release from red blood cells as a measure of membrane selectivity and analyzed how serum influences these activities. Microscopic images revealed morphological transformations of red blood cells from the normal double-disc shape to empty ghost cells upon treatment with the cationic amphiphiles. Antifungal activity, hemolysis, and morphological changes in red blood cells decreased as the percentage of serum in the culture medium was increased. In images of red blood cells treated with fluorescently labeled amphiphilic nebramine probes, the accumulation of the cationic amphiphiles in the membranes decreased as serum concentration increased. This suggests that, in addition to its known effect of preventing the deformability of red blood cells, serum prevents interactions between cationic amphiphiles and the plasma membrane. The results of this study indicate that biological activities of cationic amphiphiles are abrogated in serum. Thus, these agents are suitable for external and industrial uses but probably not for effective treatment of systemic infections.