Semisynthetic Antimycobacterial C‑3 Silicate and C‑3/C-21 Ester Derivativesof Fusidic Acid: Pharmacological Evaluation and Stability Studiesin Liver Microsomes, Rat Plasma, and Mycobacterium tuberculosis culture

Fusidic acid (FA), a natural product fusidane triterpene-based antibiotic with unique structural features, is active in vitro against Mycobacterium tuberculosis, the causative agent of tuberculosis (TB). While possessing good pharmacokinetics in man, FA is rapidly metabolized in rodents, thus complicating proof-of-concept studies in this model. Toward the repositioning of FA as an anti-TB agent, we herein describe the synthesis, activity, and metabolism of FA and semisynthesized ester derivatives in rat liver microsomes, rat plasma, and mycobacterial cell culture. FA and derivative molecules with a free C-3 OH underwent species-specific metabolism to the corresponding 3-OH epimer, 3-epifusidic acid (3-epiFA). FA was also metabolized in rat plasma to form FA lactone. These additional routes of metabolism may contribute to the more rapid clearance of FA observed in rodents. C-3 alkyl and aryl esters functioned as classic prodrugs of FA, being hydrolyzed to FA in microsomes, plasma, and Mycobacterium tubercu...