Neglected 80-Year-Old Antibiotic Could Provide a New Way To Fight Difficult-To-Treat Infections

A research team has found that Nourseothricin, an old antibiotic, could be effective against drug-resistant bacteria. Improved purification techniques have identified less toxic forms of the antibiotic, specifically Streptothricin-F, that show strong activity against Gram-negative bacteria, by binding to a bacterial ribosome subunit and inducing translation errors, offering a unique approach to combating such infections.

Better purification overcomes original renal toxicity concerns.

An old antibiotic could potentially offer much-needed protection against bacterial infections that are resistant to multiple drugs, reveals a recent study recently published in the journal PLOS Biology conducted by James Kirby and his team from Harvard Medical School, US. This discovery could present a new strategy to combat difficult-to-treat and potentially fatal infections.

Nourseothricin, a natural compound produced by a type of soil fungus, consists of multiple forms of a complex molecule known as streptothricin. When first discovered in the 1940s, this compound sparked great anticipation due to its strong efficacy against Gram-negative bacteria. These bacteria, notorious for their thick outer protective layer, are particularly resistant to other antibiotics.

But nourseothricin proved toxic to kidneys, and its development was dropped. However, the rise of antibiotic-resistant bacterial infections has spurred the search for new antibiotics, leading Kirby and colleagues to take another look at nourseothricin.

Streptothricin-F (yellow spheres) bound to the 16S rRNA (green) of the bacterial ribosome impinges on the decoding site where tRNA (purple) binds to the codon of the mRNA (blue). This interaction leads to translation infidelity (scrambled protein sequences), and the resulting death of the bacterial cell. The image was created by overlay of PDB 7UVX containing streptothricin-F (this manuscript) with PDB 7K00 containing mRNA and A-site tRNA (ref DOI: 10.7554/eLife.60482). Credit: James Kirby (CC-BY 4.0); Zoe L Watson et al., 2023, eLife, CC-BY 4.0

Early studies of nourseothricin suffered from incomplete purification of the streptothricins. More recent work has shown that the multiple forms have different toxicities with one, streptothricin-F, significantly less toxic, while remaining highly active against contemporary multidrug-resistant pathogens.

Here, the authors characterized 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, the authors showed that streptothricin-F bound extensively to a subunit of the bacterial ribosome, accounting for the translation errors these antibiotics are known to induce in their target bacteria. Interestingly, 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,” Kirby said, “we believe the streptothricin scaffold deserves further pre-clinical exploration as a potential therapeutic for the treatment of multidrug-resistant, Gram-negative pathogens.”

Kirby adds, “Isolated in 1942, streptothricin was the first antibiotic discovered with potent gram-negative activity. We find that not only is it activity potent, but that it is highly active the hardiest contemporary multidrug-resistant pathogens and works by a unique mechanism to inhibit protein synthesis.”

Reference: “Streptothricin F is a bactericidal antibiotic effective against highly drug-resistant gram-negative bacteria that interacts with the 30S subunit of the 70S ribosome” by 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 and James E. Kirby, 16 May 2023, PLOS Biology.
DOI: 10.1371/journal.pbio.3002091