9RJM
Structure of Mycobacterium tuberculosis InhA in complex with pyridomycin derivative EP196 (compound 13)
This is a non-PDB format compatible entry.
Summary for 9RJM
| Entry DOI | 10.2210/pdb9rjm/pdb |
| Related | 9RJG 9RJH 9RJI 9RJJ 9RJK 9RJL 9RJN 9RJP |
| Descriptor | Enoyl-[acyl-carrier-protein] reductase [NADH], ~{N}-[(2~{Z},5~{R},6~{S},9~{S},10~{S},11~{R})-2-butan-2-ylidene-5,11-dimethyl-10-oxidanyl-3,7,12-tris(oxidanylidene)-9-(pyridin-3-ylmethyl)-1,4-dioxa-8-azacyclododec-6-yl]-4-fluoranyl-3-oxidanyl-pyridine-2-carboxamide (3 entities in total) |
| Functional Keywords | inha mycobacterium tuberculosis pyridomycin complex inhibitor, oxidoreductase |
| Biological source | Mycobacterium tuberculosis |
| Total number of polymer chains | 6 |
| Total formula weight | 176373.67 |
| Authors | Publicola, G.,Mourey, L.,Valderrama, K.,Hartkoorn, R.,Maveyraud, L. (deposition date: 2025-06-12, release date: 2026-02-11, Last modification date: 2026-02-25) |
| Primary citation | Valderrama, K.,Horlacher, O.,Publicola, G.,Eisenring, P.,Kienle, M.,Boarbi, S.,Kiass, M.,Kordulakova, J.,Chatagnon, J.,Piveteau, C.,Leroux, F.,Savkova, K.,Zahorszka, M.,Cantrelle, F.X.,Lherbet, C.,Mourey, L.,Mikusova, K.,Mathys, V.,Aichholz, R.,Maveyraud, L.,Altmann, K.H.,Hartkoorn, R.C. Optimizing the Antibiotic Potency and Metabolic Stability of Pyridomycin Using a Semisynthetic Approach. J.Med.Chem., 69:2496-2508, 2026 Cited by PubMed Abstract: Pyridomycin is a natural product with potent activity against (), acting through direct inhibition of the fatty acid synthesis enzyme InhA. As a direct inhibitor, pyridomycin maintains activity on strains resistant to the InhA targeting prodrugs isoniazid and ethionamide. Evaluation of the drug-like properties of pyridomycin, however, found it to have poor 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 metabolic stability and with comparable or even enhanced antibacterial activity. Pharmacokinetic studies in mice, however, revealed that these gains did not reduce systemic clearance , 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 efficacy. PubMed: 41591406DOI: 10.1021/acs.jmedchem.5c02409 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.986 Å) |
Structure validation
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