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Identification of prochlorperazine dimaleate as a Sortase A inhibitor from FDA libraries for MRSA infection treatment
Abhinit Kumar1,2, Sonali Chhabra1,2, Raman Parkesh1,2
1GNRPC, CSIR - Institute of Microbial Technology Chandigarh 160036 India raman.parkesh@csir.res.in.
Abstract:
Staphylococcus aureus is acknowledged as an essential contributor to global disease burden, particularly with the emergence of methicillin-resistant S. aureus (MRSA) and vancomycin-resistant S. aureus (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. In vivo 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 S. aureus, thus reducing MRSA infection by directly targeting Sortase A. Therefore, prochlorperazine dimaleate can be utilized as an adjuvant therapy for treating MRSA infection.
Insights
This study found prochlorperazine dimaleate effectively combats methicillin-resistant Staphylococcus aureus (MRSA) by targeting the Sortase A enzyme. It reduces MRSA infection and biofilm formation, offering a potential new therapy.
Area of Science:
- Microbiology
- Pharmacology
- Drug Discovery
Background:
- Staphylococcus aureus, including MRSA and VRSA, poses a significant global health threat.
- Sortase A is a critical enzyme for MRSA virulence, making it a promising drug target.
Purpose of the Study:
- To screen FDA-approved drugs for activity against Sortase A in MRSA.
- To validate potential drug candidates for MRSA treatment.
Main Methods:
- Systematic computational and experimental drug screening.
- Antimicrobial assays, biofilm inhibition tests, and cytotoxicity assays (HepG2 cells).
- In vivo mouse thigh infection model.
Main Results:
- Six molecules showed antimicrobial activity and reduced biofilm formation against MRSA.
- Prochlorperazine dimaleate demonstrated potent MRSA activity, was non-cytotoxic to HepG2 cells, and disrupted MRSA membrane potential.
- In vivo studies confirmed prochlorperazine dimaleate's efficacy in reducing MRSA infection load.
Conclusions:
- Prochlorperazine dimaleate effectively targets Sortase A, attenuating S. aureus pathogenicity.
- This drug shows potential as an adjuvant therapy for MRSA infections.
