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

## TL;DR

Scientists modified the antibiotic fidaxomicin to make it more stable in acidic conditions while keeping its antibacterial power.

## Contribution

A new method to create acid-stable S-glycosides in fidaxomicin without harsh conditions.

## Key findings

- Modified fidaxomicin (S-Fdx) retains strong antibacterial activity against Clostridioides difficile and Clostridium perfringens.
- The acid-labile O-glycosidic bond in fidaxomicin was successfully replaced with an acid-stable S-glycosidic bond.
- Acyl derivatives of S-Fdx showed excellent potency with MIC ranges as low as 0.06–0.5 μg/mL.

## Abstract

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).