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Publication Abstract from PubMed

The antibiotic fusidic acid (FA) is used to treat Staphylococcus aureus infections. It inhibits protein synthesis by binding to elongation factor G (EF-G) and preventing its release from the ribosome after translocation. While FA, due to permeability issues, is only effective against gram-positive bacteria, the available structures of FA-inhibited complexes are from gram-negative model organisms. To fill this knowledge gap, we solved cryo-EM structures of the S. aureus ribosome in complex with mRNA, tRNA, EF-G and FA to 2.5 A resolution and the corresponding complex structures with the recently developed FA derivative FA-cyclopentane (FA-CP) to 2.0 A resolution. With both FA variants, the majority of the ribosomal particles are observed in chimeric state and only a minor population in post-translocational state. As expected, FA binds in a pocket between domains I, II and III of EF-G and the sarcin-ricin loop of 23S rRNA. FA-CP binds in an identical position, but its cyclopentane moiety provides additional contacts to EF-G and 23S rRNA, suggesting that its improved resistance profile towards mutations in EF-G is due to higher-affinity binding. These high-resolution structures reveal new details about the S. aureus ribosome, including confirmation of many rRNA modifications, and provide an optimal starting point for future structure-based drug discovery on an important clinical drug target.

Structures of the Staphylococcus aureus ribosome inhibited by fusidic acid and fusidic acid cyclopentane.,Gonzalez-Lopez A, Larsson DSD, Koripella RK, Cain BN, Chavez MG, Hergenrother PJ, Sanyal S, Selmer M Sci Rep. 2024 Jun 20;14(1):14253. doi: 10.1038/s41598-024-64868-x. PMID:38902339^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.