7UVY

A. baumannii ribosome-Streptothricin-D complex: 70S with P-site tRNA

This is a non-PDB format compatible entry.

Summary for 7UVY

• Entry DOI: 10.2210/pdb7uvy/pdb
• EMDB information: 26820
• Descriptor: 50S ribosomal protein L33, 50S ribosomal protein L5, 50S ribosomal protein L6, ... (57 entities in total)
• Functional Keywords: streptothricin, nourseothricin, antibiotic, ribosome, ribosome-rna complex, ribosome/rna
• Biological source: Acinetobacter baumannii AB0057; More
• Total number of polymer chains: 53
• Total formula weight: 2169991.12

Authors

Morgan, C.E.,Yu, E.W. (deposition date: 2022-05-02, release date: 2023-04-19, Last modification date: 2025-03-19)

Primary citation

Morgan, C.E.,Kang, Y.S.,Green, A.B.,Smith, K.P.,Dowgiallo, M.G.,Miller, B.C.,Chiaraviglio, L.,Truelson, K.A.,Zulauf, K.E.,Rodriguez, S.,Kang, A.D.,Manetsch, R.,Yu, E.W.,Kirby, J.E.
Streptothricin F is a bactericidal antibiotic effective against highly drug-resistant gram-negative bacteria that interacts with the 30S subunit of the 70S ribosome.
Plos Biol., 21:e3002091-e3002091, 2023

PubMed Abstract: The streptothricin natural product mixture (also known as nourseothricin) was discovered in the early 1940s, generating intense initial interest because of excellent gram-negative activity. Here, we establish the activity spectrum of nourseothricin and its main components, streptothricin F (S-F, 1 lysine) and streptothricin D (S-D, 3 lysines), purified to homogeneity, against highly drug-resistant, carbapenem-resistant Enterobacterales (CRE) and Acinetobacter baumannii. For CRE, the MIC50 and MIC90 for S-F and S-D were 2 and 4 μM, and 0.25 and 0.5 μM, respectively. S-F and nourseothricin showed rapid, bactericidal activity. S-F and S-D both showed approximately 40-fold greater selectivity for prokaryotic than eukaryotic ribosomes in in vitro translation assays. In vivo, delayed renal toxicity occurred at >10-fold higher doses of S-F compared with S-D. Substantial treatment effect of S-F in the murine thigh model was observed against the otherwise pandrug-resistant, NDM-1-expressing Klebsiella pneumoniae Nevada strain with minimal or no toxicity. Cryo-EM characterization of S-F bound to the A. baumannii 70S ribosome defines extensive hydrogen bonding of the S-F steptolidine moiety, as a guanine mimetic, to the 16S rRNA C1054 nucleobase (Escherichia coli numbering) in helix 34, and the carbamoylated gulosamine moiety of S-F with A1196, explaining the high-level resistance conferred by corresponding mutations at the residues identified in single rrn operon E. coli. Structural analysis suggests that S-F probes the A-decoding site, which potentially may account for its miscoding activity. Based on unique and promising activity, we suggest that the streptothricin scaffold deserves further preclinical exploration as a potential therapeutic for drug-resistant, gram-negative pathogens.

PubMed: 37192172
DOI: 10.1371/journal.pbio.3002091

Experimental method

ELECTRON MICROSCOPY (2.39 Å)