Proteomics

Dataset Information

0

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

Dataset's files

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Publications

Open Source Antibiotics: Simple Diarylimidazoles Are Potent against Methicillin-Resistant <i>Staphylococcus aureus</i>.

Klug Dana M DM   Tse Edwin G EG   Silva Daniel G DG   Cao Yafeng Y   Charman Susan A SA   Chauhan Jyoti J   Crighton Elly E   Dichiara Maria M   Drake Chris C   Drewry David D   da Silva Emery Flavio F   Ferrins Lori L   Graves Lee L   Hopkins Emily E   Kresina Thomas A C TAC   Lorente-Macías Álvaro Á   Perry Benjamin B   Phipps Richard R   Quiroga Bruno B   Quotadamo Antonio A   Sabatino Giada N GN   Sama Anthony A   Schätzlein Andreas A   Simpson Quillon J QJ   Steele Jonathan J   Shanu-Wilson Julia J   Sjö Peter P   Stapleton Paul P   Swain Christopher J CJ   Vaideanu Alexandra A   Xie Huanxu H   Zuercher William W   Todd Matthew H MH  

ACS infectious diseases 20231122 12


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 were made publicly available through the Open Source Antibiotics (OSA) consortium (https://github.com/opensourceantibiotics). Of the 18 compounds tested (at 32 μg/mL), 1  ...[more]

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