Download MendeleyMetabolically Stable Adeniylation Inhibitors of Biotin Protein Ligase as Antibacterial Agents.
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.(2025) J Med Chem 68: 3065-3087
- PubMed: 39823202
- DOI: https://doi.org/10.1021/acs.jmedchem.4c02299
- Primary Citation of Related Structures:
9DRK, 9DRN - 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 M1 . 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. Bio-9 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 Mycobacterium tuberculosis and Staphylococcus aureus ranging from 0.2 to 20 μM. The antibacterial activity of Bio-9 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 Bio-9 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.
Organizational Affiliation:
Department of Medicinal Chemistry, University of Minnesota, 308 Harvard Street SE, Minneapolis, Minnesota 55455, United States.
