Abstract
The small multidrug resistance (SMR) family of transporters are exceptional models for studying polyspecific drug transport. The family is functionally split between two major clusters: the selective Guanidinium exporters (Gdx) that selectively transport the metabolite, guanidinium, and the polyspecific quaternary ammonium compound (Qac) drug exporters that transport a range of man-made compounds with different structural properties. Members from each cluster are small, structurally similar, and only differ in what substrates they transport which makes them ideal models for investigating the molecular determinants required for multidrug transport. Using a combination of directed evolution, high throughput mutagenesis, and next generation sequencing, we identified six mutations that are necessary and sufficient to convert a selective Gdx into a polyselective quaternary ammonium transporter. Biochemical, biophysical, and structural characterization of this transporter will reveal the mechanistic basis for promiscuous transport in the SMR family.
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