Switching Residues: A Platform for the Synthesis of Fidaxomicin Antibiotics.

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.

Catch-enrich-release approach for amine-containing natural products.

Amine-containing natural products are an important class of therapeutic compounds. Herein, we report a chemoselective approach to catch and enrich amine-containing natural products, and release them as underivatized compounds. The strategy exploits the selectivity of the enzyme legumain for the specific release of amine-containing natural products.

Novel fidaxomicin antibiotics through site-selective catalysis.

Fidaxomicin (FDX) is a marketed antibiotic for the treatment of Clostridioides difficile infections (CDI). Fidaxomicin displays antibacterial properties against many Gram-positive bacteria, yet the application of this antibiotic is currently limited to treatment of CDI. Semisynthetic modifications present a promising strategy to improve its pharmacokinetic properties and also circumvent resistance development by broadening the structural diversity of the derivatives.

Semisynthetic Analogs of the Antibiotic Fidaxomicin-Design, Synthesis, and Biological Evaluation.

The glycoslated macrocyclic antibiotic fidaxomicin (, tiacumicin B, lipiarmycin A3) displays good to excellent activity against Gram-positive bacteria and was approved for the treatment of infections (CDI). Among the main limitations for this compound, its low water solubility impacts further clinical uses. We report on the synthesis of new fidaxomicin derivatives based on structural design and utilizing an operationally simple one-step protecting group-free preparative approach from the natural product.

Recent Advances in Mode of Action and Biosynthesis Studies of the Clinically Used Antibiotic Fidaxomicin.

The natural product antibiotic fidaxomicin is a marketed drug for the treatment of bacterial infections in the gut. Due to its promising activities against , the development of next generation fidaxomicin analogs is of great interest. This article reviews the most recent advances, including the elucidation of a unique mode of action by cryo-EM structures, and the efforts towards the clarification of the biosynthetic pathway.