Open Source Antibiotics: Simple Diarylimidazoles Are Potent against Methicillin-Resistant Staphylococcus aureus

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Microbiology

Background:

• Antimicrobial resistance (AMR) poses a significant global health threat.
• Private sector investment in novel antibiotic development is limited.
• Open science initiatives are crucial for addressing the AMR crisis.

Purpose of the Study:

• To discover novel antimicrobial compounds through an open-source drug discovery approach.
• To identify and optimize diarylimidazole derivatives with activity against ESKAPE pathogens, particularly MRSA.
• To investigate the structure-activity relationships and potential molecular targets of these compounds.

Main Methods:

• Screening of diarylimidazole compounds against ESKAPE pathogens.
• Hit-to-lead optimization involving synthesis of 147 new heterocyclic compounds.
• Evaluation of antimicrobial activity, intrinsic clearance, and toxicity.
• Proteomic analysis to identify potential molecular targets.

Main Results:

• 15 out of 18 initial compounds showed >90% growth inhibition against MRSA.
• Structure-activity relationships were established for the optimized compound series.
• OSA_975 demonstrated a favorable balance of potency, solubility, and reduced clearance.
• Proteomic data suggests TGFBR1 may be involved in the mechanism of action.

Conclusions:

• Diarylimidazoles represent a viable chemotype for developing new antibiotics against MRSA.
• OSA_975 is a promising lead compound with improved pharmacokinetic properties.
• The open-source approach facilitates collaborative development of urgently needed antimicrobial medicines.