Abstract
Helicobacter pylori (H. pylori) infection poses a worldwide public health crisis, as chronic infection is rampant and can lead to gastric ulcers, gastritis, and gastric cancer. Unfortunately, frontline therapies cause harmful side effects and are often ineffective due to antibiotic resistance. The FDA-approved drug auranofin is a gold complex with a Au(I) core coordinated with triethylphosphine and peracetylated thioglucose as the ligands. Auranofin is used for the treatment of rheumatoid arthritis and also displays potent activity against H. pylori. One of auranofin's modes of action involves cell death by disrupting cellular thiol-redox balance maintained by thioredoxin reductase (TrxR), but this disruption leads to unwanted side effects due to mammalian cell toxicity. Here, we developed and tested sugar-modified analogs of auranofin as potential antibiotics against H. pylori, with the rationale that modulating the sugar moiety would bias uptake by targeting bacterial cells and mitigating mammalian cell toxicity. Sugar-modified auranofin analogs displayed micromolar minimum inhibitory concentrations against H. pylori, maintained nanomolar inhibitory activity against the target enzyme TrxR, and caused reduced toxicity to mammalian cells. Taken together, our results suggest that structurally modifying the sugar component of auranofin has the potential to yield superior antibiotics for the treatment of H. pylori infection. Broadly, glyco-tailoring is an attractive approach for repurposing approved drugs.