2. Academic Validation
  3. Metabolically Stable Adenylation Inhibitors of Biotin Protein Ligase as Antibacterial Agents

Metabolically Stable Adenylation Inhibitors of Biotin Protein Ligase as Antibacterial Agents

  • J Med Chem. 2025 Feb 13;68(3):3065-3087. doi: 10.1021/acs.jmedchem.4c02299.
Qiang Liu 1,  Curtis A Engelhart 2,  Joshua B Wallach 2,  Divya Tiwari 3,  Peng Ge 1,  Adhar Manna 4,  Subhankar Panda 1,  William M McCue 1,  Tsung-Yun Wong 1,  Sachin Sharma 1,  Yahani P Jayasinghe 5,  Jessica Fuller 1,  Donald R Ronning 5,  Matthew R Bockman 1,  Ambrose Cheung 4,  Véronique Dartois 6,  Matthew D Zimmerman 6,  Dirk Schnappinger 2,  Courtney C Aldrich 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, University of Minnesota, 308 Harvard Street SE, Minneapolis, Minnesota 55455, United States.
  • 2 Department of Microbiology and Immunology, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10021, United States.
  • 3 Centre for Immunobiology, Blizard Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London E1 4NS, United Kingdom.
  • 4 Department of Microbiology & Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755, United States.
  • 5 Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States.
  • 6 Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey 07110, United States.
PMID: 39823202 DOI: 10.1021/acs.jmedchem.4c02299
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.

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