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


Dorst, Andrea; Berg, Regina; Gertzen, Christoph G W; Schäfle, Daniel; Zerbe, Katja; Gwerder, Myriam; Schnell, Simon D; Sander, Peter; Gohlke, Holger; Gademann, Karl (2020). Semisynthetic Analogs of the Antibiotic Fidaxomicin-Design, Synthesis, and Biological Evaluation. ACS Medicinal Chemistry Letters, 11(12):2414-2420.

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.

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.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Medical Microbiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Life Sciences > Biochemistry
Life Sciences > Drug Discovery
Physical Sciences > Organic Chemistry
Language:English
Date:10 December 2020
Deposited On:19 Jan 2021 13:16
Last Modified:01 Feb 2021 16:25
Publisher:American Chemical Society (ACS)
ISSN:1948-5875
OA Status:Hybrid
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1021/acsmedchemlett.0c00381
PubMed ID:33329763

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