Dual-target antibacterial agents: Bridging molecular relationships to synergistic mechanisms

Antimicrobial resistance (AMR) has emerged as a critical global health crisis, exacerbated by the stagnation of novel antibiotic discovery and declining efficacy of existing clinical agents. Dual-target antibacterial strategy has emerged as a promising approach to address this challenge. This review systematically summarizes the cutting-edge advances in dual-target antibacterial agents, covering their core design strategies, structure-activity relationships, preclinical and clinical efficacy/safety profiles, and dual-target mechanism validation. We classify these agents by key target combinations, analyze representative candidates with potent activity against drug-resistant pathogens and reduced resistance development, and identify major translational challenges including suboptimal pharmacokinetics, imbalanced target potency, and preexisting resistance. Notably, we highlight that rational designs based on classical pharmacophores enable novel target engagement, and further discuss non-classical peptide-based agents that achieve exceptional anti-resistant efficacy and undetectable resistance emergence. In conclusion, dual-target agents represent a paradigm shift in combating AMR, offering superior efficacy and lower resistance risk than traditional approaches. The integration of novel targets with artificial intelligence-driven discovery platforms will further accelerate the development of these innovative therapeutics.