Abstract
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.
Highlights
Sarecycline is a new narrow-spectrum tetracycline-class antibiotic approved for the treatment of acne vulgaris
This site partially overlaps with the anticodon stem loop (ASL) of the fully accommodated transfer RNA (tRNA) in the A site and, tetracyclines act by competing with tRNAs for binding to the ribosome
We used a collection of previously obtained Escherichia coli strains, each of which is resistant to TET due to a singlenucleotide mutation in its 16S ribosomal RNA (rRNA) (Table 1 and SI Appendix, Fig. S1) [17]
Summary
Sarecycline is a new narrow-spectrum tetracycline-class antibiotic approved for the treatment of acne vulgaris. Minocycline retains activity against bacteria-expressing tet genes, both encoding the tetracycline efflux pumps or ribosome-protection proteins Members of another group of tetracycline derivatives, such as tigecycline (TIG, Fig. 1B), are active against common tetracycline-resistant bacterial strains due to their increased affinity to the ribosome binding site, which is mediated by the 9-t-butylglycylamido. Bacterial protein synthesis is targeted and inhibited by many small-molecule compounds [1] One such class of ribosometargeting antibiotics is tetracyclines that share a common fourring naphthacene core (Fig. 1A). Tetracyclines inhibit protein synthesis by binding at the A site of the small ribosomal subunit and blocking the accommodation of an incoming aminoacyltransfer RNA (aa-tRNA) into the A site of the bacterial 70S ribosome [2,3,4].
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