80-year-old antibiotic could be used against drug-resistant bacteria

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 development of nourseothricin 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 the past 80 years have changed the antibiotic’s potential.

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 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, 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.

“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 inhibition protein synthesis,” he said in a statement.

Joan Kapusnik-Uner, PharmD, a researcher who wasn’t involved in the study as well as the senior vice president of informatics and clinical content at drug databank FDB (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 over time due to bacterial resistance emerging or because of unacceptable risk from side effects, compared to other available alternatives,” Kapusnik-Uner said.

“An example of this was streptomycin, one of the first antibiotics used against tuberculosis 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 – e.g., 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 has a PhD in molecular biology and biotechnology and is the head scientist of Culture.org. She told Medical News Today that the same approach has been taken to fight tuberculosis.

“Since there are now strains of TB that are antibiotic resistant, the repurposing and revival of old drugs has been a path that is taken by several drug developers,” Magalit said.

She said potential kidney damage as a side effect is common with many drugs. Hence, proper dosing needs to be established in order to minimize damage.

Each drug development undergoes safety tests in order to identify the extent of the possible damages. Drug development typically spans a decade. This includes all phases of clinical trials.

“We will be seeing more drugs being repurposed,” she said.

Shara Cohen, PhD, the chief executive officer and founder of Cancer Care Parcel told Medical News Today that “nourseothricin still kills drug-resistant microorganisms. Nourseothricin attacks microorganisms differently. Ribosome disruption decreases protein synthesis. Nurseothricin’s unique method kills various bacteria, even antibiotic-resistant ones.”

Cohen added that researchers have to keep up with alternatives as more drug resistance emerges.

“Nourseothricin’s wide breadth and lack of bacterial resistance makes it promising,” she said. “This medication may aid in multidrug-resistant illness treatment. Examine its effectiveness, use, and side effects.”

Kapusnik-UIner added that 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 that have antimicrobial activity, which includes the ability to inhibit or kill viruses, fungi or bacteria,” Kapusnik-Ulner said. “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 also is an important new strategy to help us to understand good health and help prevent or treat infections of the future,” she said.