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

The rising prevalence of antibiotic resistance has substantially constrained therapeutic options for bacterial infections. Beyond genetic resistance mechanisms, many refractory pathogens form biofilms or persisters, leading to antibiotic-tolerant recurrent infections. This underscores the urgent need for novel therapeutic agents. In this study, we demonstrate that Evacetrapib, a small-molecule compound with exceptionally rapid and potent bactericidal activity against methicillin-resistant Staphylococcus aureus (MRSA). Specially, it achieves complete killing within 2 hours and exhibits a minimum inhibitory concentration (MIC) of 2 μg/mL. Meanwhile, Evacetrapib minimally induces resistance and exhibits low host organ toxicity as a potentially durable antibacterial agent. In addition, Evacetrapib effectively eradicates preformed biofilms and persisters in vitro, while demonstrating sustained efficacy in a murine pneumonia model infected with clinically multiple drug resistance (MDR) S. aureus strain. Mechanistically, it spontaneously inserts into the bacterial membrane and subsequently disrupts membrane integrity and concurrently upregulates the autolysin atL to hydrolyze peptidoglycan, compromising cell wall integrity. Together, these findings establish Evacetrapib as a promising candidate for combating MRSA infections with biofilms and persisters.