Bilayer Perturbation is a Predictive Parameter for Antimalarial Development

Abstract

There is a constant need for new malaria drugs because of the perpetual development of resistance to current therapies. To facilitate the costly drug development process and to avail pharmaceutical company-vetted drug candidates to academicians who wish to explore novel strategies for preventing and treating malaria, the Medicines for Malaria Venture developed the Malaria Box. To assist in this effort, and to reduce the expenses required for drug development, we tested the 80 most potent compounds from the Malaria Box for their bilayer-perturbing effects, as sensed by a membrane-spanning channel, as a proxy for a generic membrane protein. Specifically, we used a gramicidin-based stopped-flow fluorescence assay to probe whether the compounds altered lipid bilayer properties at the concentrations where they are used to inhibit/kill the malaria parasites. Membrane-active compounds are expected to be ubiquitous modifiers of membrane protein conformational changes, meaning that they are predicted to be toxic (above some threshold concentration). Among the compounds tested, four altered membrane properties (p<0.05), and one of them MMV007384 was a potent bilayer-perturbing compound that should be used with caution, if at all. This compound was indeed known to be toxic in cell-based screens, suggesting that one can use the gramicidin-based fluorescence to test for cell toxicity.