Dual-target antibacterial agents offer superior efficacy and lower resistance risk against drug-resistant pathogens

The global health crisis of Antimicrobial Resistance (AMR) is exacerbated by the stagnation of novel antibiotic discovery and declining efficacy of existing treatments. This poses a devastating threat, particularly for immunocompromised patients and those battling multidrug-resistant (MDR) pathogens like the ESKAPE bacteria. Traditional single-target antibiotics often face rapid resistance development, leaving clinicians with limited options. The dual-target antibacterial strategy emerges as a promising approach to overcome these limitations by simultaneously engaging multiple bacterial pathways, aiming for enhanced efficacy and reduced resistance.

This review systematically summarized cutting-edge advances in dual-target antibacterial agents. Researchers covered core design strategies, structure-activity relationships, and preclinical/clinical efficacy and safety profiles. They validated dual-target mechanisms and classified agents by key target combinations. The review analyzed representative candidates demonstrating potent activity against drug-resistant pathogens and reduced resistance development, while also identifying major translational challenges inherent to this therapeutic approach.

The review identified that dual-target antibacterial agents represent a paradigm shift in combating AMR, offering superior efficacy and lower resistance risk compared to traditional approaches. It highlighted that rational designs based on classical pharmacophores enable novel target engagement. A significant finding was the discussion of non-classical peptide-based agents that achieve exceptional anti-resistant efficacy and undetectable resistance emergence. The analysis classified agents by key target combinations and detailed their structure-activity relationships (SAR), preclinical and clinical efficacy/safety profiles. Major translational challenges identified include suboptimal pharmacokinetics, imbalanced target potency, and preexisting resistance mechanisms. The review concluded that integrating novel targets with artificial intelligence-driven discovery platforms will further accelerate the development of these innovative therapeutics.

Non-classical peptide-based agents demonstrated exceptional anti-resistant efficacy and undetectable resistance emergence, showcasing a promising avenue for future development.