Optimizing the Antibiotic Potency and Metabolic Stability of Pyridomycin Using a Semisynthetic Approach
Abstract
Pyridomycin is a natural product with potent activity against Mycobacterium tuberculosis (Mtb), acting through direct inhibition of the fatty acid synthesis enzyme InhA. As a direct inhibitor, pyridomycin maintains activity on Mtb strains resistant to the InhA targeting prodrugs isoniazid and ethionamide. Evaluation of the drug-like properties of pyridomycin, however, found it to have poor in vitro metabolic stability, thus limiting its drug development potential. To address this limitation, semisynthetic derivatives were generated by replacing the metabolically labile hydroxypicolinic acid group with alternative (hetero)aromatic moieties, identifying several derivatives with improved in vitro metabolic stability and with comparable or even enhanced antibacterial activity. Pharmacokinetic studies in mice, however, revealed that these gains did not reduce systemic clearance in vivo, and neither pyridomycin nor its derivatives were effective in a murine pulmonary tuberculosis model. Overall, semisynthesis yielded more potent, P450-stable analogs, but the improvements were insufficient to provide measurable in vivo efficacy
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BibTeX
@article{valderrama2026optimizing,
title = {{Optimizing the Antibiotic Potency and Metabolic Stability of Pyridomycin Using a Semisynthetic Approach}},
author = {Katherine Valderrama and Oliver Horlacher and Gabriel Publicola and Patrick Eisenring and Maryline Kienle and Samira Boarbi and Mehdi Kiass and Jana Korduláková and Jonathan Chatagnon and Catherine Piveteau and Florence Leroux and Karin Savková and Monika Záhorszká and Francois-Xavier Cantrelle and Christian Lherbet and Lionel Mourey and Katarína Mikušová and Vanessa Mathys and Reiner Aichholz and Laurent Maveyraud and Karl-Heinz Altmann and Ruben C. Hartkoorn},
journal = {Journal of Medicinal Chemistry},
year = {2026},
month = sep,
doi = {10.1021/acs.jmedchem.5c02409},
url = {https://hal.science/hal-05663283v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Optimizing the Antibiotic Potency and Metabolic Stability of Pyridomycin Using a Semisynthetic Approach
AU - Katherine Valderrama
AU - Oliver Horlacher
AU - Gabriel Publicola
AU - Patrick Eisenring
AU - Maryline Kienle
AU - Samira Boarbi
AU - Mehdi Kiass
AU - Jana Korduláková
AU - Jonathan Chatagnon
AU - Catherine Piveteau
AU - Florence Leroux
AU - Karin Savková
AU - Monika Záhorszká
AU - Francois-Xavier Cantrelle
AU - Christian Lherbet
AU - Lionel Mourey
AU - Katarína Mikušová
AU - Vanessa Mathys
AU - Reiner Aichholz
AU - Laurent Maveyraud
AU - Karl-Heinz Altmann
AU - Ruben C. Hartkoorn
PY - 2026
DA - 2026/09/28
JO - Journal of Medicinal Chemistry
DO - 10.1021/acs.jmedchem.5c02409
UR - https://hal.science/hal-05663283v1
AB - Pyridomycin is a natural product with potent activity against Mycobacterium tuberculosis (Mtb), acting through direct inhibition of the fatty acid synthesis enzyme InhA. As a direct inhibitor, pyridomycin maintains activity on Mtb strains resistant to the InhA targeting prodrugs isoniazid and ethionamide. Evaluation of the drug-like properties of pyridomycin, however, found it to have poor in vitro metabolic stability, thus limiting its drug development potential. To address this limitation, semisynthetic derivatives were generated by replacing the metabolically labile hydroxypicolinic acid group with alternative (hetero)aromatic moieties, identifying several derivatives with improved in vitro metabolic stability and with comparable or even enhanced antibacterial activity. Pharmacokinetic studies in mice, however, revealed that these gains did not reduce systemic clearance in vivo, and neither pyridomycin nor its derivatives were effective in a murine pulmonary tuberculosis model. Overall, semisynthesis yielded more potent, P450-stable analogs, but the improvements were insufficient to provide measurable in vivo efficacy
SN - 0022-2623
SN - 1520-4804
ER -