Host defense peptide-mimicking β-peptide polymer displaying strong antibacterial activity against cariogenic Streptococcus mutans

• A host defense peptide-mimicking β -peptide polymer tbubz-(DM 50 :CH 50 ) 30 shows superior antibacterial efficiency than metronidazole against S. mutans biofilm. • The β -peptide polymer inhibits the formation of S. mutans biofilm. • The β -peptide polymer disperses mature S. mutans biofilm. • The β -peptide polymer exhibits high antibacterial activity and low cell toxicity. Cariogenic Streptococcus mutans ( S. mutans ) is a leading cause of bacterial-induced oral diseases. Current strategies to kill bacteria based on Host defense peptide (HDP) mimicking polymers hold promise to treat oral bacterial infection. Here, we explore the impact of hydrophobic subunit and chain length variation on the antibacterial and antibiofilm activity of β -peptide polymers. The physicochemical and biological properties, such as the toxicity, the antibacterial activity, and the effect on bacterial transcription of β -peptide polymers, were systematically investigated with numerous techniques. The results exhibited that the optimal β -peptide polymer has low toxicity towards human periodontal ligament fibroblasts, and β -peptide polymers (especially P3) have more excellent antibacterial activity against S. mutans than metronidazole. In addition, β -peptide polymers inhibited the reversible and irreversible bacterial adhesion during the formation of biofilms. The polymer can promote biofilm dispersion by decreasing the hydrophobicity of bacterial cells after adhering to cell surfaces. Analysis of the transcriptome for S. mutans treated with β -peptide polymers demonstrated that β -peptide polymers could reduce the cariogenicity of S. mutans by impacting the transcription of the energy and acid metabolism-related genes. β -peptide polymers are promising antimicrobial agents in clinical dentistry due to their high antibacterial efficiency and low toxicity.