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Novel Fidaxomicin Antibiotics through Site-Selective Catalysis

preprint
submitted on 01.07.2020 and posted on 02.07.2020 by David Dailler, Andrea Dorst, Daniel Schäfle, Peter Sander, Karl Gademann

Fidaxomicin (FDX) is a marketed antibiotic for the treatment Clostridium difficile infections (CDI). Although showing interesting antibacterial properties against many Gram-positive bacteria, 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 derivatives. Based on a rational design using a cryo-EM structure analysis, we implemented 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 allowed the synthesis of novel fidaxomicin analogs with promising antibacterial activities against C. difficile and M. tuberculosis.

Funding

Swiss National Science Foundation (182043)

Swiss National Science Foundation (31003A_153349/1)

Swiss Lung Association (2018-02)

History

Email Address of Submitting Author

karl.gademann@uzh.ch

Institution

University of Zurich

Country

Switzerland

ORCID For Submitting Author

0000-0003-3053-0689

Declaration of Conflict of Interest

No conflict of interest

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