Metabolically Stable Adenylation Inhibitors of Biotin Protein Ligase as Antibacterial Agents

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.