Exploring small multidrug resistance (SMR) protein interactions with metformin degradation products

The Small Multidrug Resistance (SMR) family contain membrane protein transporters that export toxic compounds from the microbial cytoplasm to the periplasm. The largest cluster in the family are the Guanidinium exporters (Gdx) that transport the bacterial metabolite, guanidinium (Gdm+). They are ubiquitously found in both bacteria and archaea genomes and plasmids associated with multidrug resistance. However, Gdxs are not known to bind or transport any antimicrobials or antiseptics. We hypothesized that the Gdxs might instead interact with metformin, a small guanidinylated antidiabetic compound, and one of the most highly prescribed drugs in the world, or its degradation products. These compounds are ubiquitous in wastewater. Using biochemical, electrophysiological and structural biology techniques, several genomic and plasmid Gdx were characterized. We show that various metformin metabolites found in wastewater are transported by the Gdx homologs, and that metformin metabolism by bacteria might rationalize the horizontal spread of Gdx-encoding genes among bacterial populations.