Phenolic Substitution in Fidaxomicin: A Semisynthetic Approach to Antibiotic Activity Across Species.

Fidaxomicin (Fdx) is a natural product antibiotic with potent activity against Clostridioides difficile and other Gram-positive bacteria such as Mycobacterium tuberculosis. Only few Fdx derivatives have been synthesized and examined for their biological activity in the 50 years since its discovery. Fdx has a well-studied mechanism of action, namely inhibition of the bacterial RNA polymerase. Yet, the targeted organisms harbor different target protein sequences, which poses a challenge for the rational development of new semisynthetic Fdx derivatives. We introduced substituents on the two phenolic hydroxy groups of Fdx and evaluated the resulting trends in antibiotic activity against M. tuberculosis, C. difficile, and the Gram-negative model organism Caulobacter crescentus. As suggested by the target protein structures, we identified the preferable derivatisation site for each organism. The derivative ortho-methyl Fdx also exhibited activity against the Gram-negative C. crescentus wild type, a first for fidaxomicin antibiotics. These insights will guide the synthesis of next-generation fidaxomicin antibiotics. © 2023 Wiley-VCH GmbH.

Citation

Erik Jung, Anastassia Kraimps, Silvia Dittmann, Tizian Griesser, Jordan Costafrolaz, Yves Mattenberger, Simon Jurt, Patrick H Viollier, Peter Sander, Susanne Sievers, Karl Gademann. Phenolic Substitution in Fidaxomicin: A Semisynthetic Approach to Antibiotic Activity Across Species. Chembiochem : a European journal of chemical biology. 2023 Sep 20:e202300570

PMID: 37728121

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