Open Source Antibiotics - Simple Diarylimidazoles are Potent Against Methicillin Resistant Staphylococcus Aureus

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 (https://en.wikipedia.org/wiki/ESKAPE) and the results made publicly available through the Open Source Antibiotics (OSA) consortium (https://github.com/opensourceantibiotics). 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 intrinsic clearance and some associated toxicity. The best overall balance of parameters was found with OSA_975, a compound with good potency, solubility and reduced intrinsic clearance in rat hepatocytes. We have progressed towards the knowledge of the molecular target of these phenotypically active compounds, with proteomic techniques suggesting TGFRB1 is potentially involved in the mechanism of action. Further development of these compounds towards antimicrobial medicines is available to anyone under the licensing terms of the project.