Synergistic strategies to rescue the last-resort antibiotic colistin

Colistin, a last-resort antibiotic, is critically important for treating multidrug-resistant Gram-negative bacterial infections, particularly those caused by carbapenem-resistant Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacteriaceae. However, its clinical utility is severely limited by dose-dependent nephrotoxicity and neurotoxicity, as well as the rapid global spread of plasmid-mediated mobile colistin resistance genes, such as mcr-1. To overcome these challenges, combination therapies have emerged as a promising strategy to enhance colistin efficacy via reducing required dosages and mitigating resistance development. This review synthesizes recent advances in colistin-based combinations, including synergies with conventional antibiotics, non-antibiotic adjuvants, antimicrobial peptides, proteins and other molecules. We also explore innovative strategies such as nanoparticles, phage-derived enzymes, in silico approaches, and targeted drug delivery systems that potentiate colistin activity. These approaches not only restore colistin susceptibility in resistant strains but also minimize toxicity and delay resistance evolution, offering a viable path toward sustaining colistin as a vital therapeutic option in the post-antibiotic era.