The ribosome in distress: the rescue crew

Protein synthesis by the ribosome is central to life. Bacterial genomes encode a vast diversity of uncharacterised proteins that protect and modulate ribosomal function.

These ‘defenders’ of the ribosome include, amongst others, ribosome rescue factors that assist ribosomes ‘stuck’ whilst producing a protein; starvation sensors that respond to ribosomal stalling due to amino acid limitation; and antibiotic resistance factors that protect the ribosome from drugs.

These proteins have crucial impacts on virulence, growth and treatability of pathogenic bacteria.

Using a panel of bacterial pathogens and guided by evolutionary analyses, we will zoom in on three classes of ribosome helper proteins: i) the emerging and spreading ABCF resistance factors that directly displace antibiotics from the ribosome, ii) RelA-SpoT Homolog stress factors implicated in antibiotic tolerance and persistent infection, and iii) RqcH virulence factors that rescue stalled ribosomes.

We will uncover their molecular mechanisms using microbiology, biochemistry, cryo-electron microscopy and next generation sequencing techniques.

Working in close collaboration with medical chemists, we will use these insights to develop new compounds to defeat bacteria that are resistant to currently available antibiotics.