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.

Genomic insights into an endophytic Streptomyces sp. VITGV156 for antimicrobial compounds

“…Many non-ribosomal peptides have antimicrobial activity, and many serve as last-resort antimicrobial agents ( Liu et al, 2019 ). Notably, at least five different NRPSs ( Table 2 ) encode VITGV156, one of which is a well-known antibacterial agent, Streptothricin ( Morgan et al, 2023 ). The products of other NRPSs remain elusive.…”

Premature aging in aneuploid yeast is caused in part by aneuploidy-induced defects in Ribosome Quality Control

“…Among the most intriguing on the list of 37 genes was RQC1, a component of the RQC pathway that resolves stalled ribosomes 36,37,76 . This was interesting because aneuploid strains are sensitive to translational inhibitor nourseothricin (NTC) that binds the ribosome to disrupt translation 13,22,[77][78][79] . Given that translation defects increase with cellular age [44][45][46] , these results raised the possibility that chromosome duplication induces defects in the RQC pathway.…”

Antimicrobial Resistance in Bacteria from Meat and Meat Products: A One Health Perspective

“…Its therapeutic use was abandoned due to its induced reversible kidney toxicity; however, new cytotoxic studies have shown that streptothricin F exhibits at least 10-fold lower toxicity than streptothricin D and nourseothricin, both in vitro and in vivo. Moreover, streptothricin F has an alternative and unique mechanism of action, interacting with the 30S subunit of the 70S ribosome [53].…”