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

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 and other bacterial pathogens.