Sarecycline inhibits protein translation in Cutibacterium acnes 70S ribosome using a two-site mechanism

Area of Science:

• Microbiology
• Structural Biology
• Pharmacology

Background:

• Acne vulgaris affects over a billion people globally, with Cutibacterium acnes (C. acnes) being a key factor in its pathogenesis.
• Antibiotic therapy targeting C. acnes is a primary treatment strategy, necessitating a deep understanding of bacterial mechanisms.

Purpose of the Study:

• To determine the high-resolution structure of the 70S ribosome from Cutibacterium acnes.
• To elucidate the mechanism of action of the narrow-spectrum antibiotic sarecycline against C. acnes.
• To identify unique structural features of the C. acnes ribosome and their potential roles.

Main Methods:

• Cryogenic electron microscopy (cryo-EM) was used to determine the 2.8-Å resolution structure of the 70S ribosome of Cutibacterium acnes.
• Comparative analysis of antibiotic binding sites and ribosomal structures across different bacterial species.

Main Results:

• Sarecycline was found to inhibit two active sites on the C. acnes ribosome: the canonical mRNA decoding center and the nascent peptide exit tunnel.
• The C. acnes ribosome possesses unique features, including two additional proteins (bS22 and bL37) not found in Escherichia coli ribosomes.
• These novel proteins, bS22 and bL37, were shown to possess antimicrobial properties and may contribute to skin microbiome homeostasis.

Conclusions:

• The dual-site inhibition by sarecycline provides a novel mechanism for its efficacy against Cutibacterium acnes.
• The identified C. acnes-specific ribosomal proteins (bS22, bL37) represent potential new targets for antimicrobial therapies and play a role in skin microbiome balance.