Metabolically Stable Adenylation Inhibitors of Biotin Protein Ligase as Antibacterial Agents.

TitleMetabolically Stable Adenylation Inhibitors of Biotin Protein Ligase as Antibacterial Agents.
Publication TypeJournal Article
Year of Publication2025
AuthorsLiu Q, Engelhart CA, Wallach JB, Tiwari D, Ge P, Manna A, Panda S, McCue WM, Wong T-Y, Sharma S, Jayasinghe YP, Fuller J, Ronning DR, Bockman MR, Cheung A, Dartois V, Zimmerman MD, Schnappinger D, Aldrich CC
JournalJ Med Chem
Volume68
Issue3
Pagination3065-3087
Date Published2025 Feb 13
ISSN1520-4804
KeywordsAnimals, Anti-Bacterial Agents, Biotin, Enzyme Inhibitors, Humans, Mice, Microbial Sensitivity Tests, Mycobacterium tuberculosis, Staphylococcus aureus, Structure-Activity Relationship
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.

DOI10.1021/acs.jmedchem.4c02299
Alternate JournalJ Med Chem
PubMed ID39823202

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