Novel fidaxomicin antibiotics through site-selective catalysis
Open Access
- 10 May 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Communications Chemistry
- Vol. 4 (1), 1-11
- https://doi.org/10.1038/s42004-021-00501-6
Abstract
Fidaxomicin (FDX) is a marketed antibiotic for the treatment of Clostridioides difficile infections (CDI). Fidaxomicin displays antibacterial properties against many Gram-positive bacteria, yet the application of this antibiotic is currently limited to treatment of CDI. Semisynthetic modifications present a promising strategy to improve its pharmacokinetic properties and also circumvent resistance development by broadening the structural diversity of the derivatives. Here, based on a rational design using cryo-EM structural analysis, we implement two strategic site-selective catalytic reactions with a special emphasis to study the role of the carbohydrate units. Site-selective introduction of various ester moieties on the noviose as well as a Tsuji–Trost type rhamnose cleavage allow the synthesis of novel fidaxomicin analogs with promising antibacterial activities against C. difficile and Mycobacterium tuberculosis.Keywords
Funding Information
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (200021_182043, 200021_182043, 200021_182043)
- Swiss Lung Association
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