Providing insight into the mechanism of action of cationic lipidated oligomers using metabolomics

Abstract

Antimicrobial resistance poses a significant challenge to healthcare systems worldwide. Novel anti-infective therapeutics are urgently needed to combat drug-resistant microorganisms. Cationic lipidated oligomers (CLOs) show promise as new antibacterial agents against Gram-positive pathogens like methicillin-resistant Staphylococcus aureus (MRSA). Understanding their molecular mechanism(s) of antimicrobial action may help design synergistic CLO treatments along with monotherapy. Here, we describe the first metabolomics study to investigate the killing mechanism(s) of CLOs against MRSA. The results of our study indicate that the CLO, C 12 -o-(BG-D)-10, had a notable impact on the biosynthesis and organization of the bacterial cell envelope. C 12 -o-(BG-D)-10 also inhibits arginine, histidine, central carbon metabolism, and trehalose production, adding to its antibacterial characteristics. This work illuminates the unique mechanism of action of C 12 -o-(BG-D)-10 and opens an avenue to design innovative antibacterial oligomers/polymers for future clinical applications.