Repurposing Evacetrapib as a membrane disruption agent inducing rapid autolysis in MRSA

Area of Science:

• Microbiology
• Infectious Diseases
• Pharmacology

Background:

• Antibiotic resistance is a growing global health threat, necessitating novel therapeutic strategies.
• Bacterial biofilms and persisters contribute to treatment failure and recurrent infections by conferring antibiotic tolerance.
• Current treatment options for infections caused by multidrug-resistant bacteria, such as MRSA, are limited.

Purpose of the Study:

• To evaluate the antibacterial efficacy of Evacetrapib against methicillin-resistant Staphylococcus aureus (MRSA).
• To investigate Evacetrapib's activity against bacterial biofilms and persisters.
• To elucidate the mechanism of action of Evacetrapib.

Main Methods:

• Minimum inhibitory concentration (MIC) determination and time-kill assays were performed.
• Efficacy against preformed biofilms and persisters was assessed in vitro.
• A murine pneumonia model was used to evaluate in vivo efficacy against a multidrug-resistant S. aureus strain.
• Mechanistic studies involved bacterial membrane insertion assays and autolysin activity measurements.

Main Results:

• Evacetrapib demonstrated rapid and potent bactericidal activity against MRSA, achieving complete killing within 2 hours at a MIC of 2 μg/mL.
• The compound effectively eradicated preformed biofilms and persisters in vitro.
• Evacetrapib showed sustained efficacy in a murine pneumonia model and exhibited low host organ toxicity.
• Mechanistically, Evacetrapib disrupts bacterial membrane integrity and upregulates autolysin (Atl) to compromise cell wall integrity.

Conclusions:

• Evacetrapib is a promising small-molecule compound with significant potential as a durable antibacterial agent against MRSA.
• Its ability to overcome biofilms and persisters, coupled with low toxicity and minimal resistance induction, makes it a valuable candidate for treating challenging S. aureus infections.