Research

A2058 methylation disrupts hydrogen bonding between the erythromycin (ERY, a macrolide) and the nucleotide.

 

Multidrug resistant ribosome. Macrolides, lincosamides and streptogramins (MLS) are structurally distinct and broad-spectrum antibiotics that inhibit protein biosynthesis by binding to the 50S large subunit of bacterial ribosome.The efficacy of MLS has rapidly eroded due to the widespread dissemination of the Erm RNA methyltransferases that catalyze the transfer of two methyl groups to a conserved adenine nucleotide (m26A2058) in the 23S rRNA of the 50S subunit. This dimethylation sterically hinders the binding of all MLS antibiotics that share the overlapping A2058, in addition to abrogating the MLS resistant bacteria from host immune recognition. Our studies seek to addresses several unresolved questions: How is the expression of erm regulated under antibiotic selection? How does Erm find its target? What are the consequences of ribosome methylation? How the next-generation antibiotics bind to the methylated ribosome?

 

A slice through of S. aureus 100S ribosome. Hibernation promoting factor (HPF) promotes 70S dimerization via the 30S-30S joining.

 

Hibernating ribosome. The bacterial 100S ribosome (dimer of 70S complexes) is important for pathogenesis, translational repression, starvation responses, and ribosome turnover. Our goal is to establish a mechanistic understanding of the biogenesis and function of the 100S ribosome in translational silencing and staphylococcal pathogenesis. This project focuses on the following unexplored questions:  What factors control the constitutive production of the 100S ribosome in S. aureus? Why are only specific mRNAs translationally repressed during ribosome hibernation? How is hibernation beneficial to ribosome stability? How is ribosome turnover linked to successful host colonization? These questions will be addressed through a multi-disciplinary approach that spans genetics, molecular biophysics, biochemistry, and whole animal infection studies.