Atomic resolution structure of the cutibacterium acnes ribosome reveals the mechanism of protein synthesis inhibition by the antibiotic sarecycline

Antibiotic resistance is a global problem. Acne vulgaris is a chronic disfiguring skin disease affecting ∼1 billion people worldwide, often having persistent negative effects on physical and mental health. Prolonged treatment of acne with broad-spectrum antibiotics results in antibiotic resistance at concerning rates in the Gram-positive anaerobe Cutibacterium acnes, the skin commensal implicated in acne pathogenesis. We determined a 2.8-Å resolution structure of the 70S ribosome of Cutibacterium acnes by cryogenic electron microscopy and discovered that sarecycline, a narrow-spectrum antibiotic against Cutibacterium acnes, may inhibit two active sites of this bacterium’s ribosome in contrast to the one site detected previously on the model ribosome of Thermus thermophilus. Apart from the canonical binding site at the mRNA decoding center, the second binding site for sarecycline exists at the nascent peptide exit tunnel, reminiscent of the macrolides class of antibiotics. The structure also revealed Cutibacterium acnes-specific features of the ribosomal RNA and proteins. Six Cutibacterium acnes ribosomal proteins bound Zn2+, providing molecular rationale for zinc supplementation in acne therapy. Unlike the ribosome of the Gram-negative bacterium Escherichia coli, Cutibacterium acnes ribosome has two additional proteins, which are also present in the ribosomes of Mycobacterium smegmatis and Mycobacterium tuberculosis. We show that these proteins have antimicrobial properties and may be involved in maintaining the healthy homeostasis of the human skin microbiome.