Breaking Biofilms: Novel Chrysophsin-1 Analogs Show Promise in Combating Dental Caries

Background: Dental caries, primarily caused by pathogenic biofilms dominated by Streptococcus mutans ((S. mutans), demands innovative antimicrobial approaches with low host toxicity to combat the increased bacterial resistance to conventional antibiotics. Despite its broad-spectrum bactericidal properties, the clinical application of chrysophsin-1 is limited by its cytotoxicity. This study aimed to develop less toxic chrysophsin-1 analogs for dental caries management.Methods: Five analogs (Chm 1, Chm 2, Chm 3, Chm 4, Chm 5) were synthesized, and their antimicrobial activities against S. mutans were tested. Antimicrobial activities and bactericidal kinetics were assessed by minimum inhibitory and bactericidal concentration methods and time-kill assays. The impact on bacterial morphology and anti-biofilm efficacy were examined using scanning electron microscopy and confocal scanning laser microscopy. Cytotoxicity was evaluated by CCK-8 assay. Structure-function relationships were studied with circular dichroism and molecular dynamics.Results: Three analogs (Chm 1, Chm 2, Chm 5) showed potent bactericidal effects on pathogens associated with dental caries with minimal cytotoxicity. Chm 1 killed bacteria within 30 minutes at 8× MBC. They disrupted biofilms by inducing membrane blebbing and pore formation, resulting in a significant reduction (>70%) in biofilm viability within 1 hour. Structural analysis confirmed that three analogs (Chm 1, Chm 2, Chm 5) mostly adopted an α - helical conformation upon binding to bacterial membranes, facilitating rapid disruption.Conclusion: These chrysophin-1 analogs demonstrate excellent antimicrobial and antibiofilm activity, coupled with high biocompatibility, and thus are promising agents for the treatment of dental caries.