{"doi":"10.1371/journal.pbio.3002091","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","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.","journal":"PLoS Biology","year":2023,"id":323347,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":37,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9625,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":437933,"name":"Yoon‐Suk Kang","orcid":"0000-0001-8115-1481","position":1,"is_corresponding":false},{"id":309450,"name":"Alex B. Green","orcid":null,"position":2,"is_corresponding":false},{"id":335794,"name":"Kenneth P. Smith","orcid":null,"position":3,"is_corresponding":false},{"id":812553,"name":"Matthew G. Dowgiallo","orcid":"0000-0001-9414-6374","position":4,"is_corresponding":false},{"id":812554,"name":"Brandon C. Miller","orcid":"0000-0002-5421-0113","position":5,"is_corresponding":false},{"id":812555,"name":"Lucius Chiaraviglio","orcid":"0000-0002-2613-6614","position":6,"is_corresponding":false},{"id":812950,"name":"Katherine A. Truelson","orcid":null,"position":7,"is_corresponding":false},{"id":309449,"name":"Katelyn E. Zulauf","orcid":null,"position":8,"is_corresponding":false},{"id":335796,"name":"Shade Rodriguez","orcid":null,"position":9,"is_corresponding":false},{"id":1038647,"name":"Anthony D. Kang","orcid":null,"position":10,"is_corresponding":false},{"id":488062,"name":"Roman Manetsch","orcid":"0000-0001-7038-6867","position":11,"is_corresponding":false},{"id":308716,"name":"Edward Yu","orcid":"0000-0001-5912-1227","position":12,"is_corresponding":false},{"id":262692,"name":"James E. Kirby","orcid":"0000-0003-0392-4500","position":13,"is_corresponding":false},{"id":652706,"name":"Christopher E. Morgan","orcid":null,"position":0,"is_corresponding":true}],"reference_count":91,"raw_metadata":null,"created_at":"2026-07-19T01:07:52.377944Z","pmid":"37192172","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}