New hope for an old antibiotic

Maria Burke

Researchers are revisiting an antibiotic previously abandoned over toxicity concerns. 

Significant advancements in modern purification techniques have allowed researchers to revisit an antibiotic dropped over toxicity concerns. It shows promise against multidrug-resistant bacteria in lab and preclinical animal models.

Isolated in 1942, nourseothricin (produced by a soil fungus) was the first antibiotic discovered with potent activity against gram-negative bacteria, which are especially hard to kill. But it proved toxic to kidneys, and its development was dropped after preclinical trials. However, nourseothricin contains several forms of a complex molecule called streptothricin, and recent studies have shown that some forms are less toxic than others.

James Kirby of Harvard Medical School and colleagues in the US investigated two highly purified forms of streptothricin, D and F.

They tested their effectiveness against gramnegative bacteria, such as Enterobacterales and Acinetobacter baumannii, which are resistant to carbapenems, a class of antibiotics used to treat severe bacterial infections. Both forms were found to be highly active, but while the D form was more powerful, it caused renal toxicity at a lower dose.

‘We find that not only is streptothricin’s activity potent, but it is highly active against the hardiest contemporary multidrug-resistant pathogens and works by a unique mechanism to inhibit protein synthesis,’ says Kirby.

‘We believe the streptothricin scaffold deserves further preclinical exploration as a potential therapeutic for the treatment of multidrugresistant, gram-negative pathogens.’

The team used cryoelectron microscopy to show that streptothricin-F binds to a subunit of the bacterial ribosome. This would explain the translation errors induced in target bacteria by these antibiotics. Significantly, the binding interaction differs from other known inhibitors of translation, suggesting it may occur when those agents are not effective.

‘Finding truly new classes of antimicrobial agent with activity against priority pathogens like carbapenem-resistant Enterobacterales and Acinetobacter baumannii are of utmost importance,’ says Tim Rawson of Imperial College London’s Centre for Antimicrobial Optimisation in the UK.

The study provides ‘optimistic observations’ that the identified compounds maintain clinically relevant activity. ‘The findings have been enabled by significant advancements in modern purification techniques allowing the authors to isolate and test purified compounds and undertake quantification of therapeutic and toxic effects of isolated compounds in both laboratory and preclinical animal models.

‘This is a nice example of how modern analytical chemistry and quantitative assays can help us revisit potential antimicrobial compounds, supporting our approach to antimicrobial resistance. It will be exciting to follow the next steps in the evaluation of the streptothricins and whether this class can be finally translated into treatment for patients.