In order to get a better understanding in the mechanism by which
tryptophan-N-formylated gramicidin (NFG) and
gramicidin kill the
malaria parasite Plasmodium falciparum in vitro, we studied the capacity of these
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 from, and
sodium flux into, erythrocytes in such a manner that it is most 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 same
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 the hypothesis that
peptide-induced parasite death is related to their capacity to induce
potassium leakage from infected erythrocytes. Finally, 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 treatment with
drug concentrations that cause full inhibition of parasite growth, these cells would not be irreversibly damaged by action of the drugs.