EFFECTS OF GRAMICIDIN AND TRYPTOPHAN-N-FORMYLATED GRAMICIDIN ON THE SODIUM AND POTASSIUM CONTENT OF HUMAN ERYTHROCYTES

In order to get a better understanding in the mechanism by which trypt ophan-N-formylated gramicidin (NFG) and gramicidin kill the malaria pa rasite Plasmodium falciparum in vitro, we studied the capacity of thes e peptides to change the potassium, as well as the sodium, composition of normal human erythrocytes, and their ability to cause cell lysis. It is shown that both peptides are able to induce potassium leakage fr om, and sodium flux into, erythrocytes in such a manner that it is mos t likely that they are able to form cation channels in the membrane of these cells. For both peptides, potassium efflux proceeds at a faster rate than sodium influx, but this difference is greater for NFG than for gramicidin. This explains the observation that gramicidin is more lytic than NFG is, even when comparing concentrations that show the sa me antimalarial activity. The finding that gramicidin is approximately 10 times more active than NFG in causing potassium efflux from normal erythrocytes, as well as in killing the malaria parasite, supports th e hypothesis that peptide-induced parasite death is related to their c apacity to induce potassium leakage from infected erythrocytes. Finall y, the observation that erythrocytes are able to restore their normal ion contents after losing more than 50% of their potassium content by incubation with NFG or gramicidin, suggests that, in vivo, and upon tr eatment with drug concentrations that cause full inhibition of parasit e growth, these cells would not be irreversibly damaged by action of t he drugs.