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Home | dactylosporangium

dactylosporangium

Fidaxomicin as a New Antibiotic Template

December 13, 2021

Fidaxomicin is a narrow-spectrum antibiotic that is specific against gram-positive bacteria. Furthermore, it is not well absorbed into the bloodstream, so it remains in the gut. Both these characteristics make it a useful drug to treat Clostridioides difficile infections. It has been in clinical use since 2011.

Fidaxomicin-resistant C. difficile is currently rare, but antibiotic resistance is always a concern. A team of scientists at the University of Zurich, Switzerland wanted to use fidaxomicin as a template to develop new antibiotics before more resistant strains evolve.

They used a rational design approach, starting with the cryo-EM structure of fidaxomicin bound to bacterial RNA polymerase. Fidaxomicin has two carbohydrates attached to it, a noviose and a rhamnose. Based on the cryo-EM structure, the C3″ on the noviose looked like a promising place to add new functional groups. The team made thirty derivatives of fidaxomicin by changing the functional groups on that carbon.

They tested the antibiotic activity of these derivatives by measuring their minimal inhibitory concentration against C. difficile. Many of the derivatives still showed antibiotic activity. Although the derivatives were not any more effective against C. difficile than fidaxomicin, this experiment is an encouraging proof of concept for the rational design of new antibiotics.

 

Dailler D, Dorst A, Schafle D, et al. Novel fidaxomicin antibiotics through site-selective catalysis. Communications Chemistry. 2021. 4:59.  doi.org/10.1038/s42004-021-00501-6.

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