Sparsomycin inhibits all ribosomes alike

Paranjpe, M.N., Leroy, E.C., Syroegin, E.A., Flemmich, L., Thaler, J., Gillard, M., Bougas, A., Kournoutou, G., Dinos, G.P., Renault, T.T., Micura, R., Innis, C.A., Polikanov, Y.S. (2026). Sparsomycin inhibits translation through a conserved mechanism across all domains of life. Nucleic Acids Res.,54, gkag761.

Sparsomycin has been known for decades to block protein synthesis by binding to the peptidyl transferase center of the ribosome. The structural literature, however, contained a contradiction: the drug appeared to bind bacterial ribosomes in a completely different way from archaeal and eukaryotic ones, which sits oddly with how strongly conserved that catalytic site is. In this collaborative study with the Polikanov and Micura groups, we combine iTP-seq with two X-ray structures of Thermus thermophilus 70S ribosomes corresponding to initiation and early elongation complexes to show that no such difference exists. In bacteria, as everywhere else, sparsomycin wedges into the A-site cleft, locking the CCA end of the P-site tRNA in place through an extensive hydrogen-bond network and physically blocking an incoming aminoacyl-tRNA from accommodating. Beyond resolving a long-standing puzzle, our work provides a concrete structural starting point for designing sparsomycin derivatives that are more selective for bacterial ribosomes.