A group of researchers have discovered that Nourseothricin, an old antibiotic, might be effective in treating infections caused by drug-resistant bacteria. Enhanced purification methods have revealed less harmful variants of the antibiotic, specifically Streptothricin-F, which demonstrates powerful activity against Gram-negative bacteria. It accomplishes this by binding to a bacterial ribosome subunit and provoking translation inaccuracies, providing a novel method for tackling such infections. Improved purification processes help address initial concerns about renal toxicity.
This antiquated antibiotic could provide much-needed defenses against bacterial infections that are impervious to numerous drugs, as per a recent study published in PLOS Biology. The study, led by James Kirby and his team from Harvard Medical School, USA, suggests this could offer a fresh tactic in the fight against hard-to-treat and potentially deadly infections.
Nourseothricin, a compound naturally produced by a particular soil fungus, is made up of various forms of a complex molecule known as streptothricin. It attracted considerable interest upon its discovery in the 1940s due to its strong efficacy against Gram-negative bacteria – bacteria known for their robust outer protective layer and resistance to other antibiotics.
However, the development of Nourseothricin was halted as it was found to be toxic to kidneys. The recent surge in antibiotic-resistant bacterial infections has reignited the quest for new antibiotics, prompting Kirby and his team to reconsider Nourseothricin.
Streptothricin-F (visualized as yellow spheres) attaches to the 16S rRNA (shown in green) of the bacterial ribosome, intruding upon the decoding site where tRNA (depicted in purple) connects to the mRNA’s codon (illustrated in blue). This interaction causes translation infidelity (scrambled protein sequences) and leads to the subsequent death of the bacterial cell.
The initial research into Nourseothricin was hindered by incomplete purification of streptothricins. More current studies have revealed that different forms possess varying levels of toxicity. One such form, streptothricin-F, is significantly less harmful while still being highly effective against current multidrug-resistant pathogens.
The research team examined the antibacterial properties, renal toxicity, and mechanism of action of highly purified variants of two distinct streptothricins, D and F. Streptothricin-D was more potent than its F counterpart against drug-resistant Enterobacterales and other bacteria but led to renal toxicity at a lower dosage. Both were particularly effective against Gram-negative bacteria.
The team demonstrated using cryo-electron microscopy that streptothricin-F bound extensively to a bacterial ribosome subunit. This binding process is unlike that of known translation inhibitors, indicating its potential utility when other agents fail.
“Considering its unique and promising activity,” said Kirby, “the streptothricin scaffold merits further pre-clinical exploration as a prospective treatment for multidrug-resistant, Gram-negative pathogens.”
Kirby further noted, “Discovered in 1942, streptothricin was the first antibiotic identified with potent gram-negative activity. Our findings show that not only is it potently active, but it also exhibits high activity against the most resilient contemporary multidrug-resistant pathogens and uses a unique mechanism to hinder protein synthesis.”
The study, “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, was published on 16 May 2023 in PLOS Biology.
Frequently Asked Questions (FAQs) about Nourseothricin
What is the primary discovery made by the research team led by James Kirby?
The team discovered that Nourseothricin, an old antibiotic, could be effective against drug-resistant bacteria. The team also found that improved purification techniques can help produce less toxic forms of the antibiotic.
What is the mechanism of action of Streptothricin-F against bacteria?
Streptothricin-F binds to a subunit of the bacterial ribosome and causes translation errors, leading to scrambled protein sequences and eventually the death of the bacterial cell. This mechanism offers a new approach to combating drug-resistant infections.
What was the initial concern with Nourseothricin, and how has it been addressed?
Initially, Nourseothricin was found to be toxic to kidneys which led to the halt of its development. However, recent studies with improved purification processes have identified a less toxic form, Streptothricin-F, that remains highly effective against multidrug-resistant bacteria.
What makes Nourseothricin a promising antibiotic in modern times?
Nourseothricin, specifically its Streptothricin-F form, has shown potent activity against contemporary multidrug-resistant pathogens. Moreover, its mechanism of action is unique, suggesting its potential use when other antibiotics fail.
What was the historical significance of Streptothricin?
Isolated in 1942, Streptothricin was the first antibiotic discovered with potent activity against Gram-negative bacteria. Despite being abandoned due to its renal toxicity, its rediscovery and reevaluation offer promising prospects against current multidrug-resistant pathogens.
More about Nourseothricin
- PLOS Biology Journal
- Harvard Medical School
- Antibiotic Resistance
- Understanding Gram-negative Bacteria