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| Title | Streptothricin F is a bactericidal antibiotic effective against highly drug-resistant gram-negative bacteria that interacts with the 30S subunit of the 70S ribosome. |
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| Journal, issue, pages | PLoS Biol, Vol. 21, Issue 5, Page e3002091, Year 2023 |
| Publish date | May 16, 2023 |
 Authors | Christopher E Morgan / Yoon-Suk Kang / Alex B Green / Kenneth P Smith / Matthew G Dowgiallo / Brandon C Miller / Lucius Chiaraviglio / Katherine A Truelson / Katelyn E Zulauf / Shade Rodriguez / Anthony D Kang / Roman Manetsch / Edward W Yu / James E Kirby /  |
| 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 ...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. |
 External links | PLoS Biol / PubMed:37192172 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 2.21 - 2.5 Å |
| Structure data | EMDB-26817, PDB-7uvv: EMDB-26818, PDB-7uvw: EMDB-26819, PDB-7uvx: EMDB-26820, PDB-7uvy: EMDB-26821, PDB-7uvz: EMDB-26822, PDB-7uw1: |
| Chemicals |  ChemComp-ZN:  ChemComp-OI9:  ChemComp-OIY:  ChemComp-MG:  ChemComp-HOH: |
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 Keywords | Ribosome/RNA / Streptothricin / Nourseothricin / Antibiotic / Ribosome / Ribosome-RNA complex |
acinetobacter baumannii ab0057 (bacteria)