9DRN

Crystal structure of Mycobacterium tuberculosis biotin protein ligase in complex with Bio-4

This is a non-PDB format compatible entry.

Summary for 9DRN

• Entry DOI: 10.2210/pdb9drn/pdb
• Related: 9DRK
• Descriptor: Biotin--[acetyl-CoA-carboxylase] ligase, 5'-deoxy-5'-(4-{5-[(3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl]pentyl}-1H-1,2,3-triazol-1-yl)adenosine (3 entities in total)
• Functional Keywords: biotin protein ligase, adenylation inhibitors, nucleoside, ligase
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 2
• Total formula weight: 56902.66

Authors

McCue, W.M.,Jayasinghe, Y.P.,Aldrich, C.C.,Ronning, D.R. (deposition date: 2024-09-25, release date: 2025-04-09)

Primary citation

Liu, Q.,Engelhart, C.A.,Wallach, J.B.,Tiwari, D.,Ge, P.,Manna, A.,Panda, S.,McCue, W.M.,Wong, T.Y.,Sharma, S.,Jayasinghe, Y.P.,Fuller, J.,Ronning, D.R.,Bockman, M.R.,Cheung, A.,Dartois, V.,Zimmerman, M.D.,Schnappinger, D.,Aldrich, C.C.
Metabolically Stable Adenylation Inhibitors of Biotin Protein Ligase as Antibacterial Agents.
J.Med.Chem., 68:3065-3087, 2025

PubMed Abstract: The antibacterial agent Bio-AMS is metabolized in vivo through hydrolysis of the central acyl-sulfamide linker leading to high clearance and release of a moderately cytotoxic metabolite . Herein, we disclose analogues designed to prevent the metabolism of the central acyl-sulfamide moiety through steric hindrance or attenuation of the acyl-sulfamide electrophilicity. was identified as a metabolically stable analogue with a single-digit nanomolar dissociation constant for biotin protein ligase (BPL) and minimum inhibitory concentrations (MICs) against and ranging from 0.2 to 20 μM. The antibacterial activity of was dependent on BPL expression level and was more than 70-fold better against a strain underexpressing BPL and, conversely, more than 5-fold less effective against a strain overexpressing BPL. Pharmacokinetic and metabolic studies demonstrated that was metabolically stable in vivo, showing negligible hydrolysis that translated to substantially reduced clearance and concomitantly boosted drug exposure and half-life compared to Bio-AMS.

PubMed: 39823202
DOI: 10.1021/acs.jmedchem.4c02299

Experimental method

X-RAY DIFFRACTION (2.98 Å)