A double tap: ribosomal protection though rRNA methylation and antibiotic displacement

Protein synthesis by the ribosome is central to all life. The ribosome is therefore a major antibiotic target, and bacteria employ numerous mechanisms to protect it.

One of the most clinically important classes of ribosome-protecting resistance factors are the 23S rRNA methyltransferases. These enzymes modify the ribosomal RNA (23S rRNA) to inhibit binding of the antibiotic.

Importantly, rRNA methyltransferases can synergise with another class of resistance factors: the antibiotic resistance (ARE) ABCFs.

These ATPases act by removing the bound antibiotic from the ribosome, and, naturally, they are more efficient at this job if the drug binds the ribosome weakly due to the rRNA modifications installed by the methyltransferases.

Acting together, the two classes of resistance factors can protect pathogens from even fully synthetic next-generation antibiotics.We will combine microbiology, biochemistry and cryo-EM to establish how these resistance factors recognise the ribosome and protect it from antibiotics.

We will uncover the mechanisms used by bacteria to ramp up production of both classes of resistance factors when challenged with antibiotics.

Taking advantage of our fundamental insights, we will collaborate with medicinal chemists on developing new antibiotics that overcome resistance either by brute force (by binding to the ribosome stronger) or by stealth (by not setting off the cellular alarm system that induce the production of resistance factors).