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

## TL;DR

Researchers tried to improve pyridomycin's drug potential by making it more stable and potent, but it still didn't work well in animal models for tuberculosis.

## Contribution

A semisynthetic approach was used to enhance pyridomycin's metabolic stability and antibacterial activity.

## Key findings

- Semisynthetic derivatives showed improved in vitro metabolic stability and comparable or enhanced antibacterial activity.
- Pharmacokinetic studies in mice revealed no reduction in systemic clearance for the derivatives.
- None of the compounds were effective in a murine pulmonary tuberculosis model.

## 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.