Chalcones as a Strategy against Bacterial Resistance: Structural Modifications and Mechanisms of Action in the Last Decade

Introduction: Bacterial infections remain one of the leading causes of human mortality, posing a significant challenge to public health. The effectiveness of antibiotics is declining due to microbial resistance, often worsened by their improper use. In this context, the search for new antibacterial agents is crucial. Chalcones, natural compounds from the flavonoid family, have attracted attention due to their broad biological activities. Structurally composed of two aromatic rings linked by an α,β-unsaturated ketone, chalcones show promising antibacterial potential, particularly against resistant strains. Methods: This review analyzed recent studies on the antibacterial activity of natural and synthetic chalcones. Emphasis was placed on structural modifications of the chalcone scaffold, their influence on antimicrobial activity, mechanisms of action, and synergism with existing antibiotics. Results: Initial research on chalcones focused on synthesis and biological activity. More recent studies have examined their antibacterial mechanisms. Modifications on the aromatic rings significantly impact activity. Synergistic effects with antibiotics have also been reported, indicating enhanced therapeutic potential. Discussion: Chalcones act on multiple bacterial targets; they inhibit biofilm formation and essential enzymes, such as DNA gyrase, GlcN-6-P synthase, and Sortase A, and disrupt efflux pumps. These actions help overcome resistance and highlight chalcones’ versatility. Conclusion: This review reinforces the importance of chalcones in antibacterial research. Their structural modification, biological activity, and multiple mechanisms of action position them as strong candidates for developing new agents to combat microbial resistance.