Publication

Publication:
Semisynthetic antimycobacterial c-3 silicate and c-3/c-21 ester derivatives of fusidic acid: Pharmacological evaluation and stability studies in liver microsomes, rat plasma, and mycobacterium tuberculosis culture

Njoroge, M
Kaur, G
Espinoza-Moraga, M
Wasuna, A
Dziwornu, G.A
Seldon, R
Taylo, D
Okombo, J
Warner, D.F
Chibale, K
Citations
Altmetric:
Abstract
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 tuberculosis culture. In contrast, C-3 silicate esters and C-21 esters were inert to hydrolysis and so did not act as prodrugs. The antimycobacterial activity of the C-3 silicate esters was comparable to that of FA, and these compounds were stable in microsomes and plasma, identifying them as potential candidates for evaluation in a rodent model of tuberculosis.
Description
Date
2019-09-13
Journal Title
Journal ISSN
Volume Title
Publisher
ACS Publications
Research Projects
Organizational Units
Journal Issue
Keywords
Tuberculosis,Fusidic acid,Metabolism,Prodrug,Silicate,Hydrolysis
Citation
Njoroge M, Kaur G, Espinoza-Moraga M, et al. Semisynthetic antimycobacterial c-3 silicate and c-3/c-21 ester derivatives of fusidic acid: pharmacological evaluation and stability studies in liver microsomes, rat plasma, and mycobacterium tuberculosis culture. ACS Infectious Diseases. 2019 Sep 13;5(9):1634-1644.
Embedded videos