Kinase Selectivity Profiling of anti-MRSA Diarylimidazoles in HEK293 Cells

ABSTRACT: Antimicrobial resistance (AMR) is widely acknowledged as one of the most serious public health threats facing the world, yet the private sector finds it challenging to generate much-needed medicines. As an alternative discovery approach, a small array of diarylimidazoles was screened against the ESKAPE pathogens and the results made publicly available through the Open Source Antibiotics (OSA) consortium. Of the 18 compounds tested (at 32 μg/mL), 15 showed >90% growth inhibition activity against MRSA alone. In the subsequent hit-to-lead optimization of this chemotype, 147 new heterocyclic compounds containing the diarylimidazole and other core motifs were synthesized, tested against MRSA and structure-activity relationships identified. While potent, these compounds have moderate to high clearance rates and some associated toxicity. The best overall balance of parameters was found with OSA_975, a compound with good potency and solubility and slow clearance in rat hepatocytes. In this study, we used multiplexed kinase inhibitor beads/mass spectrometry (MIB/MS) to study the human molecular targets of these phenotypically active compounds.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Kidney

DISEASE(S): Disease Free

SUBMITTER: Aurora Cabrera  

LAB HEAD: Matthew H. Todd

PROVIDER: PXD040208 | Pride | 2024-01-26

REPOSITORIES: Pride