Codeine dysregulates ribosome biogenesis in Escherichia coli with DNA double-strand breaks to chart path to new classes of antibiotics

Abstract

Aim: A bacterial genetics-guided approach was utilized for the discovery of new compounds affecting bacterial genome stability. Materials & methods: Fungal extracts and fractions were tested for genome instability-mediated antibacterial activity. Interaction assays and RT-qPCR were used to identify compounds that boost the activity of sub-minimum inhibitory concentration streptomycin and obtain insights on the molecular mechanisms of the primary hit compound, respectively. Results: Several extracts and fractions caused bacterial genome instability. Codeine, in synergy with streptomycin, regulates double-strand break (DSB) repair and causes bacterial ribosome dysfunction in the absence of DSBs, and dysregulation of ribosome biogenesis in a DSB-dependent manner. Conclusion: This study demonstrates a potential viable strategy that we are exploring for the discovery of new chemical entities with activities against Escherichia coli and other bacterial pathogens.