large ribosomal subunit / ribosomal small subunit biogenesis / ribosomal small subunit assembly / small ribosomal subunit / small ribosomal subunit rRNA binding / transferase activity / 5S rRNA binding / large ribosomal subunit rRNA binding / cytosolic small ribosomal subunit / cytosolic large ribosomal subunit ...large ribosomal subunit / ribosomal small subunit biogenesis / ribosomal small subunit assembly / small ribosomal subunit / small ribosomal subunit rRNA binding / transferase activity / 5S rRNA binding / large ribosomal subunit rRNA binding / cytosolic small ribosomal subunit / cytosolic large ribosomal subunit / tRNA binding / cytoplasmic translation / rRNA binding / negative regulation of translation / ribosome / structural constituent of ribosome / ribonucleoprotein complex / translation / mRNA binding / RNA binding / cytoplasm / cytosol 類似検索 - 分子機能
Ribosomal protein S21, conserved site / Ribosomal protein S21 signature. / Ribosomal protein L25, short-form / Ribosomal protein S14, bacterial/plastid / Ribosomal protein S21 superfamily / Ribosomal protein S21 / Ribosomal protein S16, conserved site / Ribosomal protein S16 signature. / Ribosomal protein S21 / Ribosomal protein L21, conserved site ...Ribosomal protein S21, conserved site / Ribosomal protein S21 signature. / Ribosomal protein L25, short-form / Ribosomal protein S14, bacterial/plastid / Ribosomal protein S21 superfamily / Ribosomal protein S21 / Ribosomal protein S16, conserved site / Ribosomal protein S16 signature. / Ribosomal protein S21 / Ribosomal protein L21, conserved site / Ribosomal protein L21 signature. / : / Ribosomal protein L6, conserved site / Ribosomal protein L6 signature 1. / Ribosomal protein L16, conserved site / Ribosomal protein L16 signature 2. / Ribosomal protein L9 signature. / Ribosomal protein L9, bacteria/chloroplast / Ribosomal protein L9, C-terminal / Ribosomal protein L9, C-terminal domain / Ribosomal protein L17 signature. / Ribosomal protein L9, C-terminal domain superfamily / Ribosomal L25p family / Ribosomal protein L25 / Ribosomal protein L36 signature. / Ribosomal protein L28/L24 superfamily / Ribosomal protein L25/Gln-tRNA synthetase, N-terminal / Ribosomal protein L25/Gln-tRNA synthetase, anti-codon-binding domain superfamily / Ribosomal protein L32p, bacterial type / Ribosomal protein L9, N-terminal domain superfamily / Ribosomal protein L9 / Ribosomal protein L9, N-terminal / Ribosomal protein L9, N-terminal domain / Ribosomal protein L28 / Ribosomal protein L35, conserved site / Ribosomal protein L35 signature. / Ribosomal protein L33, conserved site / Ribosomal protein L33 signature. / Ribosomal protein L35, non-mitochondrial / Ribosomal protein L5, bacterial-type / Ribosomal protein L6, bacterial-type / Ribosomal protein L18, bacterial-type / Ribosomal protein L19, conserved site / Ribosomal protein L19 signature. / Ribosomal protein S3, bacterial-type / Ribosomal protein S6, conserved site / Ribosomal protein S6 signature. / Ribosomal protein L36 / Ribosomal protein L36 superfamily / Ribosomal protein L36 / Ribosomal protein S19, bacterial-type / Ribosomal protein L20 signature. / Ribosomal protein L9/RNase H1, N-terminal / Ribosomal protein S7, bacterial/organellar-type / Ribosomal protein S11, bacterial-type / Ribosomal protein L27, conserved site / Ribosomal protein S13, bacterial-type / Ribosomal protein L27 signature. / Ribosomal protein S20 / Ribosomal protein S20 superfamily / Ribosomal protein S20 / Ribosomal protein S9, bacterial/plastid / Ribosomal protein S4, bacterial-type / 30S ribosomal protein S17 / Ribosomal protein S5, bacterial-type / Ribosomal protein L14P, bacterial-type / Ribosomal protein L34, conserved site / Ribosomal protein L34 signature. / Ribosomal protein S6, plastid/chloroplast / Ribosomal protein L22, bacterial/chloroplast-type / Ribosomal protein L2, bacterial/organellar-type / Ribosomal protein L35 / Ribosomal protein L35 superfamily / Ribosomal protein S2, bacteria/mitochondria/plastid / Ribosomal protein L35 / Ribosomal L28 family / Ribosomal protein L33 / Ribosomal protein L33 / Ribosomal protein L28/L24 / Ribosomal protein L33 superfamily / Ribosomal protein L30, bacterial-type / : / Ribosomal protein L18 / Ribosomal L18 of archaea, bacteria, mitoch. and chloroplast / Ribosomal protein L16 / Ribosomal protein S18, conserved site / Ribosomal protein S18 signature. / L28p-like / Ribosomal protein S16 / Ribosomal protein S16 / Ribosomal protein L20 / Ribosomal protein S16 domain superfamily / Ribosomal protein L20 / Ribosomal protein L20, C-terminal / Ribosomal protein S15, bacterial-type / Ribosomal protein L21 / Ribosomal protein L27 / Ribosomal L27 protein / Ribosomal protein L19 / Ribosomal protein L19 superfamily 類似検索 - ドメイン・相同性
Large ribosomal subunit protein uL22 / 30S ribosomal protein S10 / Small ribosomal subunit protein bS21 / Large ribosomal subunit protein bL34 / Small ribosomal subunit protein bS16 / Small ribosomal subunit protein bS18 / Small ribosomal subunit protein uS11 / Large ribosomal subunit protein bL33 / Small ribosomal subunit protein uS15 / Small ribosomal subunit protein bS20 ...Large ribosomal subunit protein uL22 / 30S ribosomal protein S10 / Small ribosomal subunit protein bS21 / Large ribosomal subunit protein bL34 / Small ribosomal subunit protein bS16 / Small ribosomal subunit protein bS18 / Small ribosomal subunit protein uS11 / Large ribosomal subunit protein bL33 / Small ribosomal subunit protein uS15 / Small ribosomal subunit protein bS20 / Large ribosomal subunit protein bL35 / Large ribosomal subunit protein bL27 / Large ribosomal subunit protein bL21 / Large ribosomal subunit protein bL32 / Large ribosomal subunit protein bL25 / Small ribosomal subunit protein uS12 / Small ribosomal subunit protein uS7 / Large ribosomal subunit protein uL13 / Large ribosomal subunit protein bL17 / Small ribosomal subunit protein uS4 / Small ribosomal subunit protein uS13 / Large ribosomal subunit protein bL36 / Large ribosomal subunit protein uL15 / Large ribosomal subunit protein uL30 / Small ribosomal subunit protein uS5 / Large ribosomal subunit protein uL18 / Large ribosomal subunit protein uL6 / Small ribosomal subunit protein uS8 / Small ribosomal subunit protein uS14 / Large ribosomal subunit protein uL5 / Large ribosomal subunit protein uL24 / Small ribosomal subunit protein uS17 / Large ribosomal subunit protein uL29 / Large ribosomal subunit protein uL16 / Small ribosomal subunit protein uS19 / Large ribosomal subunit protein uL2 / Large ribosomal subunit protein uL23 / Large ribosomal subunit protein uL4 / Large ribosomal subunit protein uL3 / Large ribosomal subunit protein bL19 / Small ribosomal subunit protein bS6 / Large ribosomal subunit protein bL9 / Large ribosomal subunit protein uL14 / Large ribosomal subunit protein bL28 / Small ribosomal subunit protein uS3 / Small ribosomal subunit protein uS9 / Small ribosomal subunit protein uS2 / Large ribosomal subunit protein bL20 類似検索 - 構成要素
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)
米国
引用
ジャーナル: PLoS Biol / 年: 2023 タイトル: Streptothricin F is a bactericidal antibiotic effective against highly drug-resistant gram-negative bacteria that interacts with the 30S subunit of the 70S ribosome. 著者: 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 ...著者: 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 / 要旨: 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.