New Antibiotic Target

Team: Graham Walker with Bryan Davies, Asha Jacob, Caroline Koehrer, Brenda Minesinger, and Shree Pandy

There is an urgent need for new classes of broad-spectrum antibiotics. Only three new classes of antibiotics have been discovered since 1962 resulting in the emergence of “superbugs” and “super-resistant superbugs”. This project has revealed a previously unknown, highly conserved RNase that plays multiple crucial cellular roles. High throughput in-vitro and in-vivo screens will be carried out to develop lead compounds that inhibit the target and could lead to the development of a new antibiotic.

This project is investigating a protein called YbeY that plays a critical role in all bacteria.

YbeY is a highly conserved protein with homologues present in nearly every sequenced bacterium. In some bacteria, YbeY is essential, whereas in others its loss results in a highly pleiotropic phenotype. YbeY’s crucial role in bacteria was initially discovered in the nitrogen fixing symbiont Sinorhizobium meliloti:

The structure and sequence similarity of YbeY to several predicted metal-dependent hydrolases would suggest a potential hydrolytic function:

YbeY is an important factor for bacterial translation but becomes essential at high temperatures:

Mapping of 16S, 23S and 5S rRNA termini reveals that YbeY influences the maturation of all three rRNAs, with a particularly strong effect on maturation at both the 5’ and 3’-ends of 16S rRNA. ybeY shows strong genetic interactions with rnc (RNase III), rnr (RNase R) and pnp (PNPase), further suggesting a role for YbeY in rRNA maturation:

YbeY proteins share structural similarities with the MID domain of the Argonaute proteins, which are central components of the eukaryotic sRNA machinery. Deletion of ybeY in S. meliloti produces similar phenotypes as a hfq mutant. Hfq, a RNA chaperone, is central to bacterial sRNA pathway. Similar to Hfq, YbeY regulates the accumulation of sRNAs as well as the target mRNAs. This study provides evidence for a conceptual parallel between prokaryotic and eukaryotic sRNA pathways:

YbeY, a previously unidentified endoribonuclease, and the exonuclease RNase R act together by a process mediated specifically by the 30S ribosomal subunit, to degrade defective 70S ribosomes but not properly matured 70S ribosomes or individual subunits. Furthermore, YbeY is the only endoribonuclease to be implicated in the critically important processing of the 16S rRNA 3' terminus:

YbeY’s key roles in stress resistance, ribosome quality control and maturation indicate why YbeY is a member of the minimal bacterial gene set and suggest that it could be a potential target for antibacterial drugs.