2. Academic Validation
  3. Optimizing the Antibiotic Potency and Metabolic Stability of Pyridomycin Using a Semisynthetic Approach

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

  • J Med Chem. 2026 Feb 12;69(3):2496-2508. doi: 10.1021/acs.jmedchem.5c02409.
Katherine Valderrama 1,  Oliver Horlacher 2,  Gabriel Publicola 3,  Patrick Eisenring 2,  Maryline Kienle 2,  Samira Boarbi 4,  Mehdi Kiass 4,  Jana Korduláková 5,  Jonathan Chatagnon 1,  Catherine Piveteau 6,  Florence Leroux 6,  Karin Savková 5,  Monika Záhorszká 5,  Francois-Xavier Cantrelle 7 8,  Christian Lherbet 9,  Lionel Mourey 3,  Katarína Mikušová 5,  Vanessa Mathys 4,  Reiner Aichholz 10,  Laurent Maveyraud 3,  Karl-Heinz Altmann 2,  Ruben C Hartkoorn 1
Affiliations

Affiliations

  • 1 Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille, F-59000 Lille, France.
  • 2 Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zürich, 8093 Zurich, Switzerland.
  • 3 Univ. Toulouse, CNRS, IPBS, 31077 Toulouse, France.
  • 4 Unit "Tuberculosis & Mycobacteria", Human Bacterial Diseases Service, Infectious Diseases in Humans, 1050 Brussels, Belgium.
  • 5 Faculty of Natural Sciences, Department of Biochemistry, Comenius University in Bratislava, Ilkovičova 6, Mlynská dolina, 842 15 Bratislava, Slovakia.
  • 6 Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, F-59000 Lille, France.
  • 7 CNRS, EMR9002 BSI Integrative Structural Biology, 59000 Lille, France.
  • 8 Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Risk Factors and Molecular Determinants of Aging-Related Diseases, F-59000 Lille, France.
  • 9 Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (LSPCMIB), UMR 5068, CNRS, Université Toulouse (UT), 31062 Toulouse, France.
  • 10 PK Sciences, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
PMID: 41591406 DOI: 10.1021/acs.jmedchem.5c02409
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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