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

doi:10.1002/cbic.202300570

“…MIC determination against C. difficile strain ATCCBAA-1382 was carried out using the broth microdilution assay, as previously described. 70 MICs reported herein refer to the concentration of the test compound suppressing growth to OD 600 < 0.15. A detailed assay protocol can be found in the Supporting Information .…”

Section: Computationsmentioning

confidence: 99%

Formal Single Atom Editing of the Glycosylated Natural Product Fidaxomicin Improves Acid Stability and Retains Antibiotic Activity

Ferrara,

Chesnokov,

Dittmann

et al. 2024

JACS Au

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Fidaxomicin (Fdx) constitutes a glycosylated natural product with excellent antibacterial activity against various Gram-positive bacteria but is approved only for Clostridioides difficile infections. Poor water solubility and acid lability preclude its use for other infections. Herein, we describe our strategy to overcome the acid lability by introducing acid-stable S-linked glycosides. We describe the direct, diastereoselective modification of unprotected Fdx without the need to avoid air or moisture. Using our newly established approach, Fdx was converted to the single atom exchanged analogue S-Fdx, in which the acid labile O-glycosidic bond to the noviose sugar was replaced by the acid stable S-glycosidic bond. Studies of the antibacterial activity of a structurally diverse set of thioglycoside derivatives revealed high potency of acyl derivatives of S-Fdx against Clostridioides difficile (MIC range: 0.12–4 μg/mL) and excellent potency against Clostridium perfringens (MIC range: 0.06–0.5 μg/mL).

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Switching Residues: Eine Plattform zur Synthese von Fidaxomicin Antibiotika

Jung,

Griesser,

Costafrolaz

et al. 2024

Angewandte Chemie

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Peripheral modification is often the main approach to optimize natural products for improved biological activity or desired physicochemical properties. This procedure inevitably increases molecular weight, often accompanied by undesired increased lipophilicity. Removing structural elements from natural products is not always tolerated. This is also the case for the antibiotic fidaxomicin (Fdx), where every structural component has been shown to be crucial for antibiotic activity. In this work, we demonstrate how the residue switching approach can maintain biological activity of Fdx derivatives by replacing the rhamnoside‐dichlorohomoorsellinate moiety of Fdx with smaller, more polar building blocks. We used palladium‐catalysed allylic substitution to selectively install N‐nucleophiles on the core of Fdx. The new derivatives were designed to mimic the binding of Fdx to the bacterial RNA polymerase. Evaluation against Mycobacterium tuberculosis, Clostridioides difficile, and the Gram‐negative model organism Caulobacter crescentus demonstrated that the newly introduced residues can restore antibiotic activity, which was further supported by on‐target RNA polymerase assays. We combined the allylic substitution with an organocatalysed novioside acylation protocol to enable the functionalisation of two vectors on Fdx in one pot. This platform greatly expands the accessible chemical space for Fdx derivatives and enables the future development of systemic Fdx antibiotics.

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Switching Residues: A Platform for the Synthesis of Fidaxomicin Antibiotics

Jung,

Griesser,

Costafrolaz

et al. 2024

Angew Chem Int Ed

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Peripheral modification is often the main approach to optimize natural products for improved biological activity or desired physicochemical properties. This procedure inevitably increases molecular weight, often accompanied by undesired increased lipophilicity. Removing structural elements from natural products is not always tolerated. This is also the case for the antibiotic fidaxomicin (Fdx), where every structural component has been shown to be crucial for antibiotic activity. In this work, we demonstrate how the residue switching approach can maintain biological activity of Fdx derivatives by replacing the rhamnoside‐dichlorohomoorsellinate moiety of Fdx with smaller, more polar building blocks. We used palladium‐catalysed allylic substitution to selectively install N‐nucleophiles on the core of Fdx. The new derivatives were designed to mimic the binding of Fdx to the bacterial RNA polymerase. Evaluation against Mycobacterium tuberculosis, Clostridioides difficile, and the Gram‐negative model organism Caulobacter crescentus demonstrated that the newly introduced residues can restore antibiotic activity, which was further supported by on‐target RNA polymerase assays. We combined the allylic substitution with an organocatalysed novioside acylation protocol to enable the functionalisation of two vectors on Fdx in one pot. This platform greatly expands the accessible chemical space for Fdx derivatives and enables the future development of systemic Fdx antibiotics.

show abstract

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

Cited by 5 publications

References 52 publications

Formal Single Atom Editing of the Glycosylated Natural Product Fidaxomicin Improves Acid Stability and Retains Antibiotic Activity

Formal Single Atom Editing of the Glycosylated Natural Product Fidaxomicin Improves Acid Stability and Retains Antibiotic Activity

Switching Residues: Eine Plattform zur Synthese von Fidaxomicin Antibiotika

Switching Residues: A Platform for the Synthesis of Fidaxomicin Antibiotics

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