Development of nanovehicles for co-delivery of colistin and ArnT inhibitors

Antimicrobial resistance (AMR) represents a critical global health challenge, with increasing prevalence among high-priority pathogens such as Pseudomonas aeruginosa. Colistin, a last-resort antibiotic, faces limitations in efficacy due to toxicity and bacterial resistance, primarily driven by lipid A modifications that impair colistin binding. In P. aeruginosa, resistance to colistin is mainly due to activation of the arn operon whose last enzyme is ArnT. This study explores a liposomal nanocarrier approach to co-deliver colistin with an ArnT inhibitor, isostevic acid (ISA), aiming to restore colistin's efficacy against resistant P. aeruginosa strain. We designed liposomes incorporating colistin in the aqueous core and ISA within the lipid bilayer, optimizing formulations to achieve stable, high-efficiency encapsulation by varying the cholesterol/egg phosphatidylcholine ratios. These co-loaded liposomes demonstrated enhanced antimicrobial activity, significantly lowering the minimum inhibitory concentration (MIC) of colistin against resistant strain. The dual-drug liposomes also achieved bactericidal effects at lower colistin concentrations compared to the free drug, attributed to the synergistic action of ISA as an adjuvant that locks colistin resistance mechanisms. The results suggest that liposome-mediated co-delivery of colistin and ISA offers a promising strategy to counteract colistin-resistant infections. This approach could improve the clinical management of multidrug-resistant P. aeruginosa and highlights the potential for liposomal systems to modulate drug release and target bacterial resistance mechanisms.