Identification of prochlorperazine dimaleate as a Sortase A inhibitor from FDA libraries for MRSA infection treatment

<i>Staphylococcus aureus</i> is acknowledged as an essential contributor to global disease burden, particularly with the emergence of methicillin-resistant <i>S. aureus</i> (MRSA) and vancomycin-resistant <i>S. aureus</i> (VRSA) strains. This study employs a systematic computational and experimental strategy to screen and validate FDA-approved drugs to target Sortase A, an essential enzyme involved in MRSA virulence. Herein, we have identified six molecules exhibiting antimicrobial potency against MRSA and reduced biofilm formation. Among the hits obtained, prochlorperazine dimaleate showed potent activity against MRSA while proving non-cytotoxic to hepatocellular Carcinoma (HepG2) cells at inhibitory concentration. Further, it also disrupts the membrane potential and creates pores inside the membrane of MRSA. <i>In vivo</i> thigh infection studies in mice showed that prochlorperazine dimaleate successfully reduced the MRSA infection load. Taken together, we herein report that prochlorperazine dimaleate attenuated the pathogenicity of <i>S. aureus,</i> thus reducing MRSA infection by directly targeting Sortase A. Therefore, prochlorperazine dimaleate can be utilized as an adjuvant therapy for treating MRSA infection.