80-Year-Old Antibiotic Is Effective Against Today’s Superbugs

A study has suggested that a new, less toxic form of an old and neglected antibiotic, nourseothricin, may protect against multidrug-resistant infections. The research is published in PLOS Biology.

Revisiting an overlooked antibiotic to tackle drug-resistant bacteria

Nourseothricin is a mixture of molecules naturally produced by Actinomyces, a type of soil bacteria. It is formed of multiple different types of streptothricin molecules such as streptothricins C, D, E and F.

Nourseothricin was first discovered in the 1940s due to its powerful effect against gram-negative bacteria, which have a thick outer layer that makes targeting them with antibiotics extremely difficult.

However, the efficacy of nourseothricin came at a price, as human trials revealed that it is toxic to the kidneys, leading to the further development of the antibiotic being abandoned.

In recent times, older antibiotics such as nourseothricin have been revisited by scientists due to the rise of antimicrobial resistance, now declared one of the top 10 global public health threats faced by humanity, according to the World Health Organization (WHO).

Early studies of nourseothricin suffered from incomplete purification of the streptothricins, though more recent research has shown that one of these molecules – streptothricin-F – has lower toxicity than other forms and is highly active against multidrug-resistant pathogens. This led the researchers in the current study to revisit and characterize these molecules for their antibacterial action and toxicity.

“Promising” activity

The researchers focused on two forms of streptothricins – D and F. Both were highly selective for gram-negative bacteria, though the D form was more effective than the F form against drug-resistant Enterobacterales and other bacterial species. However, streptothricin-D also resulted in kidney toxicity at a lower dose than streptothricin-F.

Cryo-electron microscopy revealed that streptothricin-F bound extensively to a subunit of the bacterial ribosome, part of the cells’ protein-producing machinery. This may be responsible for the errors in the translation stage of protein synthesis that these antibiotics are known to induce. Interestingly, this interaction between streptothricin and the ribosome is different from other known inhibitors of translation, suggesting streptothricin may be useful in cases 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,” says James Kirby, senior author of the study and professor of pathology at Harvard Medical School.

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 [against] the hardiest contemporary multidrug-resistant pathogens and works by a unique mechanism to [inhibit] protein synthesis.”

Reference: Morgan CE, Kang YS, Green AB, et al. Streptothricin F is a bactericidal antibiotic effective against highly drug-resistant gram-negative bacteria that interacts with the 30S subunit of the 70S ribosome. PLOS Biology. 2023;21(5):e3002091. doi: 10.1371/journal.pbio.3002091

This article is a rework of a press release issued by PLOS. Material has been edited for length and content.