Z. Batool, I. Lomakin, Y. Polikanov
Aug 12, 2020
Citations
1
Influential Citations
26
Citations
Quality indicators
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abstract
Significance Sarecycline is the first narrow-spectrum tetracycline-class antibiotic that was recently approved by the FDA for the clinical treatment of acne vulgaris. In this work, we determined two (2.8-Å and 3.0-Å) X-ray crystal structures of sarecycline bound to the initiation complex of the bacterial 70S ribosome and found that this antibiotic inhibits bacterial ribosome in part using a mechanism of direct mRNA contact, which has not been reported for any other tetracyclines so far. Moreover, our structural analysis rationalizes why sarecycline is able to overcome one of the most common mechanisms of resistance to tetracyclines among pathogenic bacteria. Thus, this work provides mechanistic insights into the function of the tetracycline class of antibiotics on the ribosome with direct clinical relevance. Sarecycline is a new narrow-spectrum tetracycline-class antibiotic approved for the treatment of acne vulgaris. Tetracyclines share a common four-ring naphthacene core and inhibit protein synthesis by interacting with the 70S bacterial ribosome. Sarecycline is distinguished chemically from other tetracyclines because it has a 7-[[methoxy(methyl)amino]methyl] group attached at the C7 position of ring D. To investigate the functional role of this C7 moiety, we determined the X-ray crystal structure of sarecycline bound to the Thermus thermophilus 70S ribosome. Our 2.8-Å resolution structure revealed that sarecycline binds at the canonical tetracycline binding site located in the decoding center of the small ribosomal subunit. Importantly, unlike other tetracyclines, the unique C7 extension of sarecycline extends into the messenger RNA (mRNA) channel to form a direct interaction with the A-site codon to possibly interfere with mRNA movement through the channel and/or disrupt A-site codon–anticodon interaction. Based on our biochemical studies, sarecycline appears to be a more potent initiation inhibitor compared to other tetracyclines, possibly due to drug interactions with the mRNA, thereby blocking accommodation of the first aminoacyl transfer RNA (tRNA) into the A site. Overall, our structural and biochemical findings rationalize the role of the unique C7 moiety of sarecycline in antibiotic action.