Synergistic combinations of antimicrobial peptides and conventional antibiotics: a strategy to delay resistance emergence in WHO priority bacteria

Abstract

Antimicrobial resistance (AMR) represents one of the most pressing global health challenges of the 21st century, significantly compromising the efficacy of conventional antibiotics. In response to this crisis, the World Health Organization (WHO) has updated its 2024 list of priority bacterial pathogens—classified into critical, high, and medium risk groups—based on their resistance mechanisms, clinical impact, and global dissemination. This comprehensive review explores the emerging therapeutic potential of antimicrobial peptides (AMPs) when used in synergistic combinations with conventional antibiotics. By dissecting the mechanistic interplay—ranging from membrane disruption and efflux pump inhibition to biofilm penetration and intracellular antibiotic delivery—we provide a structured analysis of how these dual strategies overcome specific resistance barriers. Special emphasis is given to WHO-designated pathogens such as Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus (MRSA/VRSA), Enterococcus faecium, Salmonella spp., Shigella spp., and Mycobacterium tuberculosis. Supported by extensive in vitro and in vivo data, this review catalogues dozens of successful AMP-antibiotic pairings, highlighting their fractional inhibitory concentration indices (FICI), clinical relevance, and implications for translational development. The evidence presented demonstrates that AMPs not only potentiate antibiotic action but also extend the useful lifespan of existing drugs while reducing toxicity. These findings support the advancement of AMP-based combination therapies as a next-generation strategy to contain resistance and restore the effectiveness of the antimicrobial arsenal.