Structural studies of Antibiotic-ribosome complexes

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Protein synthesis is performed on macromolecular machines called ribosomes. The essential nature of protein synthesis makes it a major target for antimicrobial agents in bacteria. However, the increase in multi-drug resistant bacteria is making our current arsenal of obsolete, and this problem is compounded by the rapid decline in the approval of new antibiotics, particularly those with novel scaffolds. To date, the majority of the available structures of clinically-relevant antibiotics are (i) on vacant ribosomal subunits, (ii) at modest resolution (3.0-3.5 Aangstrom), and (iii) are restricted to a few bacterial species. In this proposal, we propose to re-invigorate the structure-based design of ribosome inhibitors by providing critical insight into the rules governing small molecule interaction with RNA. To do this, we will determine structures of antibiotic-ribosome complexes (i) at unprecedented resolution (sub-2Aangtstrom), where water molecules, ions and even hydrogens can be visualized, (ii) within physiologically-relevant functional states, (iii) from diverse bacterial species, including pathogenic ESKAPE bacteria, as well as (iv) encompassing compounds with novel binding sites and/or scaffolds to limit cross-resistance. Additionally, these studies will not only provide insight into the mechanism of action of the inhibitors, but also into the fundamental process of protein synthesis itself.