Antimicrobial effect of pimozide by targeting ROS-mediated killing in Staphylococcus aureus

Area of Science:

• Microbiology
• Pharmacology
• Infectious Diseases

Background:

• Antimicrobial resistance in Staphylococcus aureus (S. aureus) poses a significant global health threat, increasing mortality and morbidity.
• The overuse of existing antimicrobials has accelerated the emergence of drug-resistant bacterial strains, necessitating the discovery of novel therapeutic agents.

Purpose of the Study:

• To investigate the antibacterial efficacy of pimozide (PMZ) against various bacterial strains, including methicillin-sensitive (MSSA) and methicillin-resistant (MRSA) S. aureus.
• To elucidate the mechanism of action of PMZ, including its effects on bacterial viability, virulence factors, and biofilm formation.

Main Methods:

• Minimum inhibitory concentration (MIC) determination for MSSA and MRSA.
• Assessment of bacterial cell viability and membrane permeability following PMZ treatment.
• Quantification of α-hemolysin production and biofilm formation.
• In vivo efficacy testing in a Caenorhabditis elegans infection model.
• Evaluation of hemolytic effects on human and chicken blood tissues.

Main Results:

• Pimozide demonstrated complete inhibition of MSSA and MRSA growth at 12.5 μg/mL and 100 μg/mL (1× MIC), respectively.
• PMZ (2× MIC) eliminated bacterial viability within 90 minutes via reactive oxygen species (ROS)-mediated killing, without compromising cell membrane integrity.
• PMZ suppressed α-hemolysin production and biofilm formation by approximately 50% at 1× MIC and effectively detached mature biofilms.
• In vivo studies showed PMZ effectively cleared S. aureus infections in C. elegans, improving survival by 90%, and exhibited no hemolytic activity.

Conclusions:

• Pimozide exhibits potent broad-spectrum antibacterial activity against S. aureus, including resistant strains.
• The mechanism involves ROS-mediated cell death and inhibition of key virulence factors like α-hemolysin and biofilm.
• PMZ demonstrates safety and efficacy in preclinical models, suggesting its potential as a novel therapeutic agent for S. aureus infections.