Characterization of the potent in vitro and in vivo antimalarial activities of ionophore compounds

Abstract

Large-scale in vitro screening of different types of ionophores previously pinpointed nine compounds that were very active and selective in vitro against Plasmodium falciparum; their in vitro and in vivo antimalarial effects were further studied. Addition of the ionophores to synchronized P. falciparum suspensions revealed that all P. falciparum stages were sensitive to the drugs. However, the schizont stages were three- to ninefold more sensitive, and 12 h was required for complete parasite clearance. Pretreatment of healthy erythrocytes with toxic doses of ionophores for 24 to 48 h showed that the activity was not due to an irreversible effect on the host erythrocyte. No preferential ionophore adsorption in infected or uninfected erythrocytes occurred. On the other hand, ionophore molecules strongly bound to serum proteins since increasing the serum concentration from 2 to 50% led to almost a 25-fold parallel increase in the ionophore 50% inhibitory concentration. Mice infected with the malaria parasites Plasmodium vinckei petteri or Plasmodium chabaudi were successfully treated with eight ionophores in a 4-day suppressive test. The 50% effective dose after intraperitoneal administration ranged from 0.4 to 4.1 mg/kg of body weight, and the therapeutic indices were about 5 for all ionophores except monensin A methyl ether, 5-bromo lasalocid A, and gramicidin D, whose therapeutic indices were 12, 18, and 344, respectively. These three compounds were found to be curative, with no recrudescence. Gramicidin D, which presented impressive antimalarial activity, requires parenteral administration, while 5-bromo lasalocid A has the major advantage of being active after oral administration. Overall, the acceptable levels of toxicity and the good in vivo therapeutic indices in the rodent model highlight the interesting potential of these ionophores for the treatment of malaria in higher animals.

Polyketide Polyethers

“…Plasmodium falciparum is sensitive to these compounds at all stages, but the schizont stages were most sensitive with 12 hours required for complete parasite clearance (8). In infected mice treated with 10 mg/kg of monensin, all mice were cured compared with one third of the mice given nigericin.…”

“…More recently, antimalarial activity has also been reported for monensin, nigericin, and lasalocid (8,9). Plasmodium falciparum is sensitive to these compounds at all stages, but the schizont stages were most sensitive with 12 hours required for complete parasite clearance (8).…”

“…Monensin acts as a specific ionophore to dissipate ionic gradients across cell membranes and is used widely in veterinary medicine and as a food additive in animal husbandry (7). Antimalarial activity has also been reported (8,9). Monensin is the best studied of the polyether ionophore antibiotics, and it was the first to have its gene cluster sequenced (2).…”

Ionophores

“…The use of monensin to improve efficiency of milk production in dairy cattle has been approved in the U.S. (FDA, 2004). Experimental studies on the use of ionophores for the treatment of malaria (Adovelande and Schrevel, 1996;Gumila et al, 1997), mycobacteriosis (Brumbaugh et al, 2004;Greenstein et al, 2009), lead poisoning (Hamidinia et al, 2002) and as an aid in the potentiation of anti-cancer therapies (Griffin et al, 1993;Shaik et al, 2001) have been conducted. These studies were conducted in cell culture or as challenge studies in laboratory animals and have shown some degree of efficacy.…”

Effects of Polyether Ionophores on the Protective Immune Responses of Broiler Chickens against Angara Disease and Newcastle Disease Viruses

“…Traditionally, two major kinds of drugs have been used as coccidostats: (1) drugs that act against parasite metabolism, such as halofunginone and amprolium, and (2) drugs that act through changing the ion transport and disrupting osmotic balance, such as lasalocid, monensin, salinomycin, maduramycin (Allen and Fetterer, 2002). Polyether ionophores (also called carboxylic antibiotics) are commonly incorporated into animal or poultry feed and are active against parasites including coccidia (Eimeria) and Plasmodium (Gumila et al, 1996(Gumila et al, , 1997, as well as against Grampositive organisms and mycoplasmas (Dutta and Devriese, 1984;Butaye et al, 2003). Avian coccidiosis is a protozoan disease caused by Eimeria species (Allen and Fetterer, 2002).…”