Semisynthetic Analogs of the Antibiotic Fidaxomicin-Design, Synthesis, and Biological Evaluation

Andrea Dorst; Regina Berg; Christoph G W Gertzen; Daniel Schäfle; Katja Zerbe; Myriam Gwerder; Simon D Schnell; Peter Sander; Holger Gohlke; Karl Gademann

doi:10.1021/acsmedchemlett.0c00381

Semisynthetic Analogs of the Antibiotic Fidaxomicin-Design, Synthesis, and Biological Evaluation

ACS Med Chem Lett. 2020 Oct 14;11(12):2414-2420. doi: 10.1021/acsmedchemlett.0c00381. eCollection 2020 Dec 10.

Authors

Affiliations

¹ Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
² Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf and John von Neumann Institute for Computing (NIC), Institute of Biological Information Processing (IBI-7: Structural Biochemistry) & Jülich Supercomputing Centre (JSC), Forschungszentrum Jülich, 40225 Düsseldorf, Germany.
³ Institute of Medical Microbiology, University of Zurich, Gloriastrasse 28/30, 8006 Zurich, Switzerland.
⁴ National Center for Mycobacteria, University of Zurich, Gloriastrasse 28/30, 8006 Zurich, Switzerland.

Abstract

The glycoslated macrocyclic antibiotic fidaxomicin (1, tiacumicin B, lipiarmycin A3) displays good to excellent activity against Gram-positive bacteria and was approved for the treatment of Clostridium difficile infections (CDI). Among the main limitations for this compound, its low water solubility impacts further clinical uses. We report on the synthesis of new fidaxomicin derivatives based on structural design and utilizing an operationally simple one-step protecting group-free preparative approach from the natural product. An increase in solubility of up to 25-fold with largely retained activity was observed. Furthermore, hybrid antibiotics were prepared that show improved antibiotic activities.