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.

Graphical abstract

Keywords::

• codeine
• DNA double-strand breaks
• fungal metabolites
• ribosome
• streptomycin

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.4155/fdd-2023-0005

Acknowledgments

V Amarh and PK Arthur express their heartfelt gratitude to Felix Selasi Dewornu, Leonard Asare and Elikem Kisser for various forms technical assistance offered to this project during their internship in our laboratory.

Disclaimer

The views expressed in this publication are those of the author(s) and not necessarily those of African Academy of Sciences, NEPAD Agency, Wellcome Trust or the UK government.

Financial disclosure

V Amarh and PK Arthur were supported by funds from a World Bank African Centres of Excellence grant (ACE02-WACCBIP: Awandare) and a DELTAS Africa grant (DEL-15-007: Awandare). The DELTAS Africa Initiative is an independent funding scheme of the African Academy of Sciences’s Alliance for Accelerating Excellence in Science in Africa and supported by the New Partnership for Africa’s Development Planning and Coordinating Agency (NEPAD Agency) with funding from the Wellcome Trust (107755/Z/15/Z: Awandare) and the UK government. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.