Modification of the intestinal microbiota with Enterobacteriaceae-specific oligonucleotide antimicrobials as a novel approach to improve metabolic health

Imbalances in the microbiota due to overgrowth of Enterobacteriaceae is associated with numerous metabolic conditions- most notably obesity. We describe an oligonucleotide antimicrobial, Transcription Factor Decoys (TFDs) that competitively inhibit the Crp-FNR transcription factor highly conserved amongst Enterobacteriaceae and is critical for the regulation of stress response and survival under anaerobic conditions. A nanoparticulate formulation delivers the TFDs to the cytoplasm of E. coli, as visualised by confocal microscopy, rapidly reduced viable bacteria under anaerobic conditions. In vitro data showed FNR TFD decreased up to log10 6 CFU/ml of coliforms within the Enterobacteriaceae family while other families remained relatively undisturbed; similarly when delivered orally to wild-type mice in vivo, Enterobacteriaceae were significantly reduced while other key bacterial populations were unaffected. This demonstrates that TFDs can be used to make precise changes to the microbiota and has utility in testing associations between dysbiosis and disease potentially leading to the development of microbiota targeted therapeutics to tackle obesity.