Alkali Cation- and Borate-Binding States of Tartrolon Antibiotics.

Abstract

The borate-binding polyketide macrolide natural products are a long-known family of bacterial antibiotics and antiparasitic agents. Among these, tartrolon E is highly potent and selective in killing eukaryotic parasites while sparing mammalian cells. However, it has been challenging to obtain, fully chemically define, and formulate the tartrolons. Here, we describe a streamlined route to obtain pure tartrolon E as a highly crystalline material. The method yielded crystals of tartrolon E, the analysis of which revealed the stable chelation of a sodium counterion. Using this chemically defined material, additional experiments permitted quantitative cation exchange with alkali-metal cations, suggesting a relative binding affinity of Li⁺ > Na⁺ > K⁺. In cases where complex mixtures of boronated/deboronated tartrolons are obtained, we developed methods to cleanly deboronate tartrolon E, yielding tartrolon D, and to reintroduce the boron atom back to the complex. Overall, we demonstrate practical methods to deliver chemically defined complexes of tartrolon E, which will facilitate further study of the intriguing biological activities of this potently bioactive macrolide family and enable the preclinical development of these important antiparasitic and antibiotic agents.