The forgotten 80-year-old antibiotic could provide a new way to fight hard-to-treat infections

Green glow bacteria

A research team has found that Nourseothricin, an older antibiotic, can be effective against resistant bacteria. Improved purification techniques have identified less toxic forms of antibiotics, namely Streptothricin-F, which show potent activity against gram-negative bacteria, by binding to a bacterial ribosomal subunit bacteria and cause translation errors, offering a unique approach to combating such infections.

Better purification overcomes the original nephrotoxicity concern.

An old antibiotic has the potential to offer much-needed protection against infections caused by multi-drug-resistant bacteria, reveals a recent study published in the journal Nature. PLOS Biology conducted by James Kirby and his team from Harvard Medical School, USA. This finding could offer a new strategy to combat difficult-to-treat and potentially fatal infections.

Nourseothricin, a natural compound produced by a soil fungus, consists of many forms of a complex molecule called streptothricin. When it was first discovered in the 1940s, this compound caused great anticipation due to its strong effectiveness against gram-negative bacteria. These bacteria are known for their thick protective outer layer, which is particularly resistant to other antibiotics.

But nourseothricin proved to be toxic to the kidney and its growth was eliminated. However, the rise of antibiotic-resistant bacterial infections has prompted the search for new antibiotics, leading Kirby and colleagues to take a different look at nourseothricin.

The 80-year-old antibiotic is forgotten

Streptothricin-F (yellow sphere) bound to the 16S rRNA (green) of the bacterial ribosome touches the decoding site where the tRNA (purple) binds to the codon of the mRNA (blue). This interaction leads to dishonest translation (disordered protein sequences) and to bacterial cell death. Images were generated by coating a streptothricin-F-containing PDB 7UVX (this manuscript) with a PDB 7K00 containing the A-site mRNA and 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

Initial studies of nourseothricin were incompletely purged of streptothricin. More recent studies have shown that multiple forms of toxicity differ with one, streptothricin-F, being significantly less toxic, while maintaining high activity against modern multidrug-resistant pathogens.

Here, the authors describe the antibacterial effects, nephrotoxicity, and mechanism of action of two different forms of streptothricin, D and F, highly purified. The D form is more potent than the F form against resistant Enterobacterales and other bacteria.[{» attribute=»»>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


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