Health
Old drugs show new potential for superbugs
Older antibiotics may offer much-needed protection against multidrug-resistant bacterial infections, according to a new study published May 16.th in open access journals PLOS biology By James Kirby et al., Harvard Medical School, USA. The findings may offer new ways to combat infections that are difficult to treat and potentially fatal.
study: Streptothricin F is an effective bactericidal antibiotic against highly drug-resistant Gram-negative bacteria that interacts with the 30S subunit of the 70S ribosome.. Image credit: Kateryna Kon / Shutterstock
Nurseothricin is a natural product made by soil fungi and contains multiple forms of a complex molecule called streptotricin. Its discovery in the 1940s raised great expectations as a powerful drug against Gram-negative bacteria. Gram-negative bacteria are particularly difficult to kill with other antibiotics because of their thick protective outer layer. However, Nurseothricin was found to be toxic to the kidneys and its development was discontinued. But the rise of antibiotic-resistant bacterial infections has spurred a search for new antibiotics, prompting Kirby and his colleagues to reconsider nurseothricin.
Streptothricin F (yellow sphere) bound to bacterial ribosomal 16S rRNA (green) collides with the decoding site where the tRNA (purple) binds to an mRNA codon (blue). This interaction causes translation infidelity (protein sequence disorder), resulting in bacterial cell death. This image was created by overlaying PDB 7UVX (this manuscript) containing streptotricin F and PDB 7K00 containing mRNA and A-site tRNA (reference DOI: 10.7554/eLife.60482). Image credit: James Kirby (CC-BY 4.0, https://creativecommons.org/licenses/by/4.0/); Zoe L. Watson et al., 2023, eLife, CC-BY 4.0 (https://creativecommons.org/licenses/by/4.0/)
Early studies of nurseothricin were incomplete in the purification of streptothricin. More recent studies have shown that multiple forms have different virulence, one of which, streptotricin F, remains highly active against modern multidrug-resistant pathogens. , which has been shown to be significantly less toxic. Here, the authors characterized the antimicrobial activity, nephrotoxicity, and mechanism of action of two different highly purified forms of streptothricin D and F. The D form was more potent than the F form against drug-resistant Enterobacterial and other bacterial species, but nephrotoxicity is observed at low doses. Both were highly selective for Gram-negative bacteria.
The authors used cryo-electron microscopy to show that streptothricin-F binds extensively to subunits of bacterial ribosomes, and these antibiotics are known to cause target bacteria. Explained the translation error. Interestingly, this binding interaction differs from other known translation inhibitors, suggesting that it could be used when these agents are ineffective.
“Based on its unique and promising activity, we believe that the streptothricin scaffold deserves further preclinical investigation as a potential therapeutic agent for multidrug-resistant Gram-negative pathogens,” said Professor Kirby.
Professor Kirby added, “Streptothricin, isolated in 1942, was the first antibiotic discovered to have potent Gram-negative activity. , found to be the most active among modern multidrug-resistant pathogens and to operate by a unique mechanism,” he added. Inhibits protein synthesis. ”
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