Optimizing the Antibiotic Potency and Metabolic Stability of Pyridomycin Using a Semisynthetic Approach

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.