New Study Reveals Old Antibiotic’s Potential in Combating Multi-Drug Resistant Bacterial Infections

A groundbreaking study, to be published today in the renowned open access journal PLOS Biology, highlights the promising role of an age-old antibiotic in offering much-needed protection against multi-drug resistant bacterial infections. Led by James Kirby and a team from Harvard Medical School, the research sheds light on a new avenue for combating challenging and potentially life-threatening infections.

The antibiotic in question, nourseothricin, is a natural product derived from a soil fungus and consists of various forms of a complex compound called streptothricin. Its discovery in the 1940s raised significant expectations for its effectiveness against Gram-negative bacteria, known for their resilient outer protective layers that render them highly resistant to conventional antibiotics. Unfortunately, nourseothricin was found to be toxic to the kidneys, leading to the discontinuation of its development.

However, the alarming surge of antibiotic-resistant bacterial infections has prompted scientists, including Kirby and his colleagues, to reexamine the potential of nourseothricin as a therapeutic solution. By revisiting this forgotten antibiotic, researchers aim to unlock its hidden properties and explore its efficacy against multi-drug resistant strains.

In the early stages of studying nourseothricin, incomplete purification of the streptothricins posed a challenge. However, recent research has revealed that different forms of streptothricins exhibit varying levels of toxicity. Notably, streptothricin-F demonstrates significantly lower toxicity while maintaining high efficacy against contemporary multidrug-resistant pathogens. In this study, the authors conducted a comprehensive characterization of two purified forms of streptothricins, namely D and F, examining their antibacterial action, renal toxicity, and mechanism of action.

Comparing the two forms, it was found that the D form exhibited greater potency against drug-resistant Enterobacterales and other bacterial species. However, it also caused renal toxicity at a lower dosage. Both streptothricins displayed a high degree of selectivity for Gram-negative bacteria.

Employing cryo-electron microscopy, the authors successfully demonstrated that streptothricin-F binds extensively to a bacterial ribosome subunit. This binding mechanism explains the translation errors induced by these antibiotics in their target bacteria. Importantly, the observed interaction differs from that of other known translation inhibitors, implying potential usefulness of streptothricin-F in cases where conventional agents prove ineffective.

“Based on unique, promising activity,” Kirby points out, “we believe the streptothricin scaffold deserves further pre-clinical exploration as a potential therapeutic for the treatment of multidrug-resistant, Gram-negative pathogens.”

“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 inhibition protein synthesis.”

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