Fdx was reported to be stable in a pH range of 4-6. 17 At lower pH, acidic degradation renders the molecule instable. With the increased stability of our S-glycosidic analogue towards acid-mediated nucleophilic substitution, we next wanted to study the effect of exposure to acidic conditions as they are encountered in gastric fluid. Despite the poor water solubility of Fdx, the solubility and thus, the exposure to the acidic conditions are significantly impacted by the presence of solubility enhancers. In the currently used film-coated tablet Dificlir, Fdx is supplied along with microcrystalline cellulose, and sodium starch glycollate, which can enhance the solubility or dissolution rate. To mimic physiological conditions in a simplified setting, the conditions were chosen close to simulated gastric fluid without pepsin (SGFsp, pH 1.2). MeCN was used as a cosolvent to account for the poor water solubility of Fdx/S-Fdx at low pH. The addition of MeCN however decreases the acid strength, requiring the pH to be adjusted. Fdx/S-Fdx were exposed to acidic conditions at 37 °C for 2 h, before the solutions were neutralized and the antibacterial activity was investigated. We observed full degradation of Fdx within 2 h under the acidic conditions, simulating the acidic environment in the stomach (Fig. , Suppl. Fig. ). The acidic exposure significantly diminished the antibacterial activity of Fdx. An increase in the minimum inhibitory concentration (MIC) of Fdx of more than 250fold against C. diff. and 125-fold increase against C. perfringens (see Fig. and Suppl. Tab. 7) was found when comparing the antibacterial activity of Fdx with, and without pre-exposure to the acidic environment. In contrast, S-Fdx remained intact (Fig. ) upon exposure to the same conditions and largely maintained its activity (1-to 4-fold increase against C. diff.; 4-to 8-fold increase against C. perfringens, see Fig. and Suppl. Tab. 7). These findings clearly demonstrate the superior acid stability of S-Fdx brought about by exchanging a single atom in the molecule. The improved acid stability along with the promising activity against C. perfringens even after treatment under acidic conditions (MIC: 0.5 µg/mL, see Fig. ) render S-Fdx derivatives promising to extend the application portfolio of Fdx to stomach infections.