Valderrama, Katherine, Horlacher, Oliver, Publicola, Gabriel, Aichholz, Reiner, Maveyraud, Laurent, Altmann, Karl-Heinz and Hartkoorn, Ruben C. (2026) Optimizing the antibiotic potency and metabolic stability of pyridomycin using a semisynthesis approach. Journal of medicinal chemistry, 69 (3). pp. 2496-2508.

Abstract

Pyridomycin is a natural product with potent antibiotic activity on Mycobacterium tuberculosis (Mtb) that acts through the direct inhibition of the ACP-enoyl reductase (InhA) of type II fatty acid synthesis. As a direct inhibitor, pyridomycin can overcome established resistance to InhA targeting prodrugs such as isoniazid and ethionamide, making it an attractive candidate for drug development. However, evaluation of the drug-like properties of pyridomycin revealed poor in vitro metabolic stability, thus posing an important barrier for drug development. To address this limitation, a semi-synthetic approach was employed to generate pyridomycin derivatives, where the metabolically labile hydroxypicolinic acid moiety was replaced by other (hetero)aromatic groups. Biological assessment of these derivatives confirmed the importance of hydroxyl and aromatic nitrogen for pyridomycin binding and InhA inhibition. At the same time, several derivatives showed superior in vitro metabolic stability over the parent natural product and exhibited similar or improved in vitro antibiotic activity on Mtb. Despite these promising in vitro results, pharmacokinetic studies in mice revealed that improved metabolic stability in liver microsomes did not translate to reduced systemic clearance in vivo. Consistent with this finding, neither pyridomycin nor its derivatives demonstrated efficacy in a murine model of pulmonary tuberculosis. In summary, semisynthesis of pyridomycin has allowed to generate derivatives of pyridomycin with improved potency and cytochrome P450 stability, but these improvements were insufficient to achieve measurable in vivo.

Item Type:	Article
Date Deposited:	07 Apr 2026 00:45
Last Modified:	07 Apr 2026 00:45
URI:	https://oak.novartis.com/id/eprint/58220