Physicochemical characterization, solubilization, and stabilization of a macrolide antibiotic

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

“…Next, we investigated the configurational stability of the per-O-acylated 1-thiosugars under the reaction conditions. Treating 1-thiosugar 6a with 1 mol % Cu[ClO 4 ] 2 ·6H 2 O in MeCN did not lead to anomeric epimerization on the reaction time scale, also not after addition of acetic acid to mimic the acidic conditions in the presence of Fdx (p K a 6.8) (see Figures S1 and S2). Thus, introducing the β-anomer of 1-thiosugars allows us to control the configuration of the glycosidic linkage, which proved challenging to access for glycosylation of the aglycone .…”

“…Fdx was reported to be stable in a pH range of 4–6 . At lower pH, acidic degradation renders the molecule instable. ,, With the increased stability of our S-glycosidic analogue toward acid-mediated nucleophilic substitution, we next wanted to study the effect of exposure to acidic conditions as they are encountered in gastric fluid.…”

“…At lower pH, acidic degradation renders the molecule instable. ,, With the increased stability of our S-glycosidic analogue toward 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.…”

Emerging concerns of infectious diseases and drug delivery challenges

“…Microbes also tend to infect the organs which are protected by tissue or blood barrier for example Taenia solium , Cryptococcus neoformans found in central nervous system while C. trachomatis lies in the eye. To treat these types of infection, drugs need to administer in blood and to reach the target site, drugs should have ability to pass through the endothelial cells and pumped back to the systemic circulation [36] .…”