Targeting multidrug resistant Staphylococcus aureus with cationic chlorpromazine‐peptide conjugates

Quaternary ammonium peptide conjugates were synthesized to target multidrug resistant pathogens. Compound CPWL showed excellent potential against multidrug resistant S. aureus strains with no cytotoxicity and found to target saFabI as revealed by MD simulation studies.

Abstract

Antimicrobial resistance is a serious public health risk. Its severity is fueled on an unprecedented scale, necessitating the demand for novel antimicrobial scaffolds aimed at novel targets. Herein, we present cationic chlorpromazine peptide conjugates that are rationally intended to targetmultidrug-resistant (MDR) bacteria. The most potent compound, CPWL, of all the conjugates evaluated, showed promising antibacterial activity against clinical, MDR S. aureus, with no cytotoxicity. The molecular docking experiments confirmed that CPWL possessed a very high affinity for S. aureus enoyl reductase (saFabI). Furthermore, CPWL antibacterial action against saFabI was further corroborated by MD simulation studies. Thus, our findings highlight cationic chlorpromazine as a promising scaffold for the development of saFabI inhibitors to target severe staphylococcal infections.

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