Abstract
With drug resistance threatening our first line antimalarial treatments, novel chemotherapeutics need to be developed. Ionophores have garnered interest as novel antimalarials due to their theorized ability to target unique systems found in the Plasmodium-infected erythrocyte. In this study, during the bioassay-guided fractionation of the crude extract of Streptomyces strain PR3, a group of cyclodepsipeptides, including valinomycin, and a novel class of cyclic ethers were identified and elucidated. Further study revealed that the ethers were cyclic polypropylene glycol (cPPG) oligomers that had leached into the bacterial culture from an extraction resin. Molecular dynamics analysis suggests that these ethers are able to bind cations such as K+, NH4+ and Na+. Combination studies using the fixed ratio isobologram method revealed that the cPPGs synergistically improved the antiplasmodial activity of valinomycin and reduced its cytotoxicity in vitro. The IC50 of valinomycin against P. falciparum NF54 improved by 4–5-fold when valinomycin was combined with the cPPGs. Precisely, it was improved from 3.75 ± 0.77 ng/mL to 0.90 ± 0.2 ng/mL and 0.75 ± 0.08 ng/mL when dosed in the fixed ratios of 3:2 and 2:3 of valinomycin to cPPGs, respectively. Each fixed ratio combination displayed cytotoxicity (IC50) against the Chinese Hamster Ovary cell line of 57–65 µg/mL, which was lower than that of valinomycin (12.4 µg/mL). These results indicate that combinations with these novel ethers may be useful in repurposing valinomycin into a suitable and effective antimalarial.
Highlights
Ionophores are ion carriers that can selectively bind cations and transport them down electrochemical gradients [1]
Streptomyces strain PR3 was identified as a producer of potent antiplasmodial compounds during a series of experiments to screen filamentous actinobacteria [16]
Each fraction was tested for antiplasmodial activity against the drug-sensitive strain P. falciparum, NF54
Summary
Ionophores are ion carriers that can selectively bind cations and transport them down electrochemical gradients [1]. Ionophores typically have a hydrophilic interior in which they coordinate cations, and a hydrophobic exterior which allows them to transport cations through lipid membranes. This ability allows ionophores to disrupt electrochemical gradients in cells, resulting in cellular disruption and death [2]. Ionophores exhibit a range of antibiotic activities, including antibacterial [1], antifungal [3], anticancer [4] and antiviral [5]. Most ionophores are barred from being used as chemotherapeutic agents in humans due to their lack of host selectivity [2]. Ionophores are gathering interest as novel antimalarial drugs, with a number of studies showing that ionophores display potent antimalarial activity in vitro and in vivo [2,6,7,8,9,10]
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