(746f) Antagonistic Cooperativity between Antimalarials Controlling b-Hematin Crystallization By Attenuation of Step Pinning

The pathologies of malaria, gout, kidney stones, and other diseases involve crystallization and its inhibition is the target of drugs that are often combined for increased efficacy. Hematin is a toxic byproduct of hemoglobin digestion in malaria parasites and suppression of its sequestration into inert hemozoin crystals is a favored pathway for parasite elimination. Current state-of-the-art antimalarial regimens combine two or more hematin crystallization blockers, though extensive efforts have failed to deliver molecular-level understanding of the synergy or antagonism between the partner drugs. Here we use a combination of scanning probe microscopy and molecular modeling and demonstrate that drug pairs, whose constituents employ distinct mechanisms of hematin crystallization inhibition, kink blocking and step pinning, exhibit both synergistic and antagonistic cooperativity depending on the drug combination and applied concentrations. Whereas synergism between two crystal growth modifiers is expected, the antagonistic cooperativity defies current crystal growth models. We demonstrate that kink blockers reduce the line tension of step edges, which facilitates both the nucleation of new crystal layers and step propagation through the gates created by step-pinners. The molecular viewpoint on cooperativity between crystallization modifiers provides guidance on the pairing of drugs in malaria combination therapies. The proposed mechanisms suggest strategies to control pathological and physiological crystallization in living organisms, and to understand crystallization in ubiquitous natural and engineered systems, which occurs in complex multicomponent environments.