Ribosome protection by antibiotic resistance ATP-binding cassette protein

Area of Science:

• Molecular Biology
• Structural Biology
• Microbiology

Background:

• The ribosome is a primary target for numerous antibiotics.
• Antibiotic resistance, particularly to ribosome-targeting drugs, is a growing clinical concern.
• ATP-binding cassette (ABC-F) proteins are known to confer resistance, but their mechanisms remain largely uncharacterized.

Purpose of the Study:

• To elucidate the mechanism by which MsrE confers resistance to macrolide antibiotics.
• To determine the structural basis of MsrE interaction with the ribosome.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was used to determine the structure of MsrE in complex with the ribosome in its ATP-bound state.
• Biochemical assays were employed to validate the functional implications of the observed structure.

Main Results:

• The cryo-EM structure reveals that MsrE binds to the ribosomal exit site, a distinct location compared to other known ribosomal protection proteins.
• A unique needle-like structure formed by MsrE's domain linker projects into the peptidyl-transferase center and nascent peptide exit tunnel.
• MsrE binding induces conformational changes in the ribosome, leading to the release of bound antibiotics.

Conclusions:

• MsrE confers macrolide resistance through a novel mechanism involving direct interaction with the ribosomal exit site.
• The unique structural arrangement of MsrE facilitates the ejection of antibiotics from the ribosome.
• This mechanism is likely conserved among ABC-F type ribosome protection proteins, offering potential new avenues for combating antibiotic resistance.