Oxadiazolone Derivatives: Powerful Tools to Reduce Staphylococcus aureus Infection

Area of Science:

• Microbiology and Infectious Diseases
• Medicinal Chemistry
• Biochemistry

Background:

• Staphylococcus aureus is a high-priority pathogen due to antimicrobial resistance, virulence, and ability to form biofilms and persist intracellularly.
• Difficult-to-treat S. aureus infections necessitate the development of novel chemical classes with unique mechanisms of action.
• Oxadiazolone-core derivatives (OXs) represent a potential new chemotype for antibacterial drug discovery.

Purpose of the Study:

• To investigate the antibacterial activity of oxadiazolone derivatives against planktonic, intracellular, and biofilm-associated Staphylococcus aureus.
• To identify the molecular targets of active oxadiazolone derivatives using activity-based protein profiling and mass spectrometry.

Main Methods:

• Screening of oxadiazolone derivatives for antibacterial activity against S. aureus in planktonic, intracellular, and biofilm models.
• Determination of minimum inhibitory concentrations (MICs) for active compounds.
• Activity-based protein profiling (ABPP) coupled with mass spectrometry to identify enzyme targets.

Main Results:

• MpPPOX demonstrated bactericidal activity against extracellular S. aureus with an MIC comparable to vancomycin.
• iBPOX primarily inhibited intracellular S. aureus replication, while HPOX significantly impaired initial biofilm formation.
• ABPP identified that HPOX targets enzymes involved in biofilm formation and virulence; iBPOX and MpPPOX target multiple (Ser/Cys)-based enzymes, including FabH for MpPPOX.

Conclusions:

• Oxadiazolone derivatives exhibit diverse activities against S. aureus, including extracellular, intracellular, and antibiofilm effects.
• These compounds act via covalent binding to multiple (Ser/Cys)-based enzymes, highlighting their multitarget nature.
• Oxadiazolones are versatile chemotypes with potential as broad-spectrum antimicrobial agents, capable of enhancing existing therapies.