Repurposing Candesartan Cilexetil as Antibacterial Agent for MRSA Infection

Area of Science:

• Microbiology
• Infectious Diseases
• Pharmacology

Background:

• Staphylococcus aureus is a major cause of hospital-acquired infections.
• Methicillin-resistant S. aureus (MRSA), biofilms, and persisters present significant treatment challenges due to high antibiotic tolerance.
• Novel antimicrobial agents are crucial for effective treatment of S. aureus infections.

Purpose of the Study:

• To investigate the antimicrobial potential of candesartan cilexetil (CC) against Staphylococcus aureus.
• To evaluate CC's efficacy against antibiotic-tolerant bacterial forms like MRSA, biofilms, and persisters.
• To explore CC's mechanism of action and in vivo effectiveness.

Main Methods:

• Determined minimal inhibitory concentrations (MICs) and minimal bactericidal concentrations (MBCs) of CC against S. aureus.
• Assessed CC's cytotoxicity and potential for inducing drug resistance.
• Evaluated synergistic effects of CC with gentamicin and tobramycin.
• Tested CC's efficacy in inhibiting MRSA biofilm formation and killing persisters.
• Analyzed CC's mechanism of action on bacterial cell membranes and structure.
• Assessed CC's in vivo antibacterial effects in a murine skin abscess model.

Main Results:

• CC demonstrated strong antimicrobial activity against S. aureus (MICs 8-16 μg/ml, MBCs 16-32 μg/ml).
• CC exhibited low cytotoxicity and low resistance potential.
• CC showed synergistic effects with gentamicin and tobramycin.
• CC effectively inhibited MRSA biofilm formation (16-64 μg/ml) and killed persisters (4-8 × MIC).
• CC disrupted bacterial membrane permeability and cell structure.
• CC displayed in vivo antibacterial effects in a murine model.

Conclusions:

• Candesartan cilexetil possesses significant antimicrobial properties against S. aureus, including resistant strains and challenging forms.
• CC's ability to disrupt bacterial cell integrity and its synergistic potential highlight its therapeutic promise.
• These findings suggest CC could be a valuable agent for treating S. aureus infections.