Discovery of guanidinium salt incorporating cinnamic acid skeleton as new antibacterial agents against Gram-positive bacteria

Abstract

The global infection rates caused by multidrug-resistant bacteria continue to rise, while the pipeline for novel antibiotics is increasingly drying up, highlighting the urgent need to develop new antimicrobial agents. Drawing inspiration from the amphiphilic structure of cationic antimicrobial peptides (AMPs), a collection of amphiphilic guanidinium salts incorporating cinnamic acid skeleton was designed and prepared. Bioactivity screening revealed that compound 10c exhibited excellent inhibitory effects against Gram-positive bacteria, with MIC values ranging from 1 to 2 μg/mL, comparable to the clinically used drug vancomycin. Further evaluation demonstrated that 10c possessed negligible hemolytic activity, infrequent resistance acquisition, low cytotoxicity, fast bactericidal action, and good plasma stability, indicating strong potential for further development. Additionally, 10c not only effectively prevented biofilm formation but also significantly disrupted pre-formed biofilms. Mechanistic studies revealed that 10c achieved selective membrane targeting by specifically interacting with phosphatidylglycerol present in the bacterial cell membrane. This interaction triggered membrane depolarization, increased membrane permeability, leading to elevated intracellular ROS levels and escape of cellular contents, ultimately accelerating bacterial death. More importantly, 10c significantly reduced bacterial burden and mitigated tissue inflammation, outperforming vancomycin in a murine skin abscess model. In summary, these results indicated that compound 10c was a membrane-active antimicrobial candidate with promising potential for further development.