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


Jung, Erik; Kraimps, Anastassia; Dittmann, Silvia; Griesser, Tizian; Costafrolaz, Jordan; Mattenberger, Yves; Jurt, Simon; Viollier, Patrick H; Sander, Peter; Sievers, Susanne; Gademann, Karl (2023). Phenolic Substitution in Fidaxomicin: A Semisynthetic Approach to Antibiotic Activity Across Species. Chembiochem, 24(24):e202300570.

Abstract

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-negative 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.

Abstract

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-negative 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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Medical Microbiology
05 Vetsuisse Faculty > Veterinärwissenschaftliches Institut > Institute of Food Safety and Hygiene
07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:610 Medicine & health
540 Chemistry
570 Life sciences; biology
Scopus Subject Areas:Life Sciences > Biochemistry
Life Sciences > Molecular Medicine
Life Sciences > Molecular Biology
Physical Sciences > Organic Chemistry
Language:English
Date:14 December 2023
Deposited On:27 Dec 2023 11:31
Last Modified:29 Jun 2024 01:41
Publisher:Wiley-VCH Verlag
ISSN:1439-4227
OA Status:Hybrid
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1002/cbic.202300570
PubMed ID:37728121
  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)