Despite development of the antibiotic nourseothricin being halted decades ago due to potential toxicity to kidneys, researchers say the abandoned, 80-year-old antibiotic could be useful in fighting drug-resistant bacteria.
Medical advances may now make it possible to use the drug, which was discovered during World War II and could possibly be used as an alternative for difficult-to-treat drug-resistant bacterial infections, reports Medical News Today.
In a study published in the journal PLOS Biology, researchers led by Dr James Kirby, a professor of pathology at Harvard Medical School, reports that nourseothricin might provide much-needed protection against multi-drug resistant bacterial infections.
Nourseothricin is a natural product made by a soil fungus containing multiple forms of a complex molecule called streptothricin.
History of nourseothricin
Scientists discovered nourseothricin in the 1940s and had high hopes it could be a powerful agent against gram-negative bacteria, which due to their outer membrane and efflux pumps, are especially hard to kill with other antibiotics.
However, the drug’s development was halted once researchers discovered it was toxic to kidneys.
Now, the rise of antibiotic-resistant bacterial infections has prompted a search for new antibiotics, leading Kirby’s team to take another look at nourseothricin.
Medical advances over the past 80 years have changed the antibiotic’s potential, and the researchers said early studies of nourseothricin suffered from incomplete purification of the streptothricins.
Recently, scientists say they have shown that multiple forms have different toxicities with one, streptothricin-F, significantly less toxic, while remaining highly active against contemporary multidrug-resistant pathogens.
In their current study, the research team characterised the antibacterial action, renal toxicity, and mechanism of action of highly purified forms of two different streptothricins, D and F.
The D form was more powerful than the F form against drug-resistant Enterobacterales and other bacterial species but caused renal toxicity at a lower dose. Both were highly selective for gram-negative bacteria.
Using cryo-electron microscopy, researchers showed streptothricin-F bound extensively to a subunit of the bacterial ribosome, which makes proteins for bacteria through a process called translation. This accounts for the translation errors these antibiotics are known to induce in their target bacteria.
The binding interaction is distinct from other known inhibitors of translation, suggesting it may find use when those agents are not effective.
“Based on unique, promising activity, we believe the streptothricin scaffold deserves further pre-clinical exploration as a potential therapeutic for the treatment of multidrug-resistant, gram-negative pathogens,” the researchers said.
Kirby said streptothricin was first isolated in 1942 and was the first antibiotic discovered with potent gram-negative activity.
“Not only is it activity potent, but it is highly active the hardiest contemporary multidrug-resistant pathogens and works by a unique mechanism to inhibition protein synthesis,” he said.
New uses for older drugs
Joan Kapusnik-Uner, PharmD, a researcher who wasn’t involved in the study and who is the senior vice-president of informatics and clinical content at drug databank First Databank, told Medical News Today that revisiting or reviving older drug compounds is a viable strategy.
She said medications can work better now because of advances in purification and synthetic methods as well as the implementation of alternative dosing strategies or routes of administration.
“Antibiotics have been infrequently revived, in that their use in practice had waned or decreased due to bacterial resistance emerging or because of unacceptable risk from side effects, compared with other available alternatives.
“An example was streptomycin, one of the first antibiotics used against TB and then for other gram-negative bacterial infections,” she said.
“Its clinical utility ran its course due to bacterial resistance emerging. The revival of this drug occurred when combination therapies – like penicillin and streptomycin – were recommended for synergy in regimens to treat serious gram-positive bacterial infections such as Enterococcal heart valve infection.”
Grace Angelique Magalit, who has a PhD in molecular biology and biotechnology and is the head scientist of Culture.org, said the same approach has been taken to fight TB.
“Since there are now strains of TB that are antibiotic resistant, the repurposing and revival of old drugs has been a path taken by several drug developers.”
She said potential kidney damage as a side effect is common with many drugs, so proper dosing is needed, to minimise damage.
Keeping up with drug-resistant bacteria
Kapusnik-UIner said microorganism resistance is part of an organism’s natural life cycle and will continue to be a thorn in researchers’ sides.
“We should all look forward to more of this type of research that revisits older compounds with antimicrobial activity, which includes the ability to inhibit or kill viruses, fungi or bacteria. There are many compounds found in nature or are semi-synthetic – slightly altered from nature – that have been investigated and gone through some of the rigorous development phases.
“Human microbiome research is an important new strategy to help prevent or treat infections of the future.”
Study details
Streptothricin F is a bactericidal antibiotic effective against highly drug-resistant gram-negative bacteria that interacts with the 30S subunit of the 70S ribosome
Christopher Morgan,Yoon-Suk Kang, James Kirby, et al.
Published in PLOS Biology on 16 May 2023
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.
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