Dataset for "Phenolic Substitution in Fidaxomicin: A Semisynthetic Approach to Antibiotic Activity Across Species"

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Supporting information for

Phenolic Substitution in Fidaxomicin: A Semisynthetic Approach to Antibiotic Activity Across Species

Erik Jung,[a] Anastassia Kraimps,[a] Silvia Dittmann,[b] Tizian Griesser,[c] Jordan Costafrolaz,[d] Yves Mattenberger,[d] Simon Jurt,[a] Patrick H. Viollier,[d] Peter Sander,[c] Susanne Sievers,[b] and Karl Gademann*[a]

[a] E. Jung, A. Kraimps, S. Jurt, Prof. Dr. K. Gademann Department of Chemistry, University of Zurich 8057 Zürich (Switzerland)
E-mail: [e-mail]
[b] S. Dittmann, Dr. S. Sievers
Department of Microbial Physiology and Molecular Biology Institute of Microbiology
Center for Functional Genomics of Microbes
University of Greifswald
Greifswald (Germany)
[c] T. Griesser, Prof. Dr. P. Sander Institute of Medical Microbiology University of Zurich
Zurich (Switzerland)
[d] J. Costafrolaz, Dr. Y. Mattenberger, Prof. Dr. P. H. Viollier Department of Microbiology and Molecular Medicine Faculty of Medicine, University of Geneva
Geneva (Switzerland)

Abstract of the corresponding publication:

Fidaxomicin (Fdx) is a natural product antibiotic with potent activity against Clostridioides difficile and other Gram-positive bacteria such as Mycobacterium tuberculosis. Only a few Fdx derivatives have been synthesized and examined for their biological activity in the 50 years since its discovery. Fdx has a well-studied mechanism of action, namely inhibition of the bacterial RNA polymerase. Yet, the targeted organisms harbor different target protein sequences, which poses a challenge for the rational development of new semisynthetic Fdx derivatives. We introduced substituents on the two phenolic hydroxy
groups of Fdx and evaluated the resulting trends in antibiotic activity against M. tuberculosis, C. difficile, and the Gram-neg- ative model organism Caulobacter crescentus. As suggested by the target protein structures, we identified the preferable derivatisation site for each organism. The derivative ortho- methyl Fdx also exhibited activity against the Gram-negative C. crescentus wild type, a first for fidaxomicin antibiotics. These insights will guide the synthesis of next-generation fidaxomicin antibiotics.