Novel fidaxomicin antibiotics through site-selective catalysis

David Dailler; Andrea Dorst; Daniel Schäfle; Peter Sander; Karl Gademann

doi:10.1038/s42004-021-00501-6

Novel fidaxomicin antibiotics through site-selective catalysis

Commun Chem. 2021 May 10;4(1):59. doi: 10.1038/s42004-021-00501-6.

Authors

David Dailler^#¹, Andrea Dorst^#¹, Daniel Schäfle², Peter Sander^{2

3}, Karl Gademann⁴

Affiliations

¹ Department of Chemistry, University of Zurich, Zurich, Switzerland.
² Institute of Medical Microbiology, University of Zurich, Zurich, Switzerland.
³ National Center for Mycobacteria, University of Zurich, Zurich, Switzerland.
⁴ Department of Chemistry, University of Zurich, Zurich, Switzerland. karl.gademann@chem.uzh.ch.

^# Contributed equally.

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.

Abstract

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