In a groundbreaking research collaboration between the University of Leiden in the Netherlands and the John Innes Centre in the UK, a new approach to antibiotic discovery has been unveiled. The project focused on repurposing existing drugs for their potential as antibiotics, leading to the identification of a highly promising candidate with a unique mechanism for killing drug-resistant bacteria.

The researchers screened a chemical library consisting of 352 small molecules that have been used in human therapies for cancer. These molecules, known as isoquinoline sulfinamides, had not been previously tested for their ability to combat harmful bacteria such as Escherichia coli. Out of the compounds screened, 12 were found to inhibit bacterial growth, with the most potent one being chemically optimized and referred to as LEI-800.

Further investigation revealed that LEI-800 exhibited antimicrobial activity against E. coli and K. pneumoniae, two Gram-negative bacteria commonly associated with hospital-acquired infections. The research team’s discovery that resistant strains contained mutations in genes encoding the bacterial enzyme DNA gyrase highlighted the compound’s target. By binding to E. coli gyrase and inhibiting its activity in a novel manner, LEI-800 presents a promising new approach to combating drug-resistant bacteria.

Potential for Future Antibiotic Development

The urgent need for new antibiotics to address the global health crisis of drug-resistant bacteria underscores the significance of this study. The development of an entirely new class of molecules targeting Gram-negative bacteria, which have become increasingly resistant to current drugs, offers hope for the future of antibiotic therapy. Dr. Dmitry Ghilarov of the John Innes Centre emphasizes the potential of repurposing existing compounds for antibiotic discovery, citing the cost-effective nature of this approach.

The researchers’ use of cryo-EM microscopy to confirm the binding of LEI-800 to E. coli gyrase highlights the innovative techniques employed in this study. The unique binding pocket of the compound and its interaction with the target enzyme suggest that it could complement existing antibiotics, providing an additional line of defense against resistant bacteria. Dr. Ghilarov envisions further discoveries to come from this approach, emphasizing the vast potential for drug discovery using repurposed compounds.

The study’s findings open up new possibilities for antibiotic development, offering a glimpse into the future of drug discovery. By repurposing existing compounds and exploring their potential as antibiotics, researchers have uncovered a novel way to target drug-resistant bacteria. The optimization of LEI-800 and its progression towards clinical trials and commercialization signify a significant milestone in the quest for effective antibiotic therapy.


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