Repurposing loratadine to reverse colistin resistance in <i>Klebsiella pneumoniae</i> through targeting lipid A modification

The emergence of multidrug-resistant <i>Klebsiella pneumoniae</i> poses a significant challenge to clinical treatment and public health. Strategies combining antibiotics with FDA-approved non-antibiotic drugs have recently attracted attention as a promising approach to overcome antibiotic resistance. In this study, we systematically evaluated the synergistic effect of the antihistamine loratadine in combination with colistin against <i>K. pneumoniae</i>. Our results demonstrate that loratadine significantly restores the bactericidal activity of colistin against colistin-resistant <i>K. pneumoniae</i> both <i>in vitro</i> and <i>in vivo</i>, without increasing toxicity, while also delaying the development of colistin resistance. Mechanistic investigations using fluorescence-based assays and proteomic analysis revealed that loratadine acts as a potent adjuvant for colistin, effectively restoring its activity against colistin-resistant <i>K. pneumoniae</i> by interfering with lipid A modification. This phenomenon is further supported by the downregulation of lipid A-modifying enzyme-related protein EptB. In addition, the combination of loratadine and colistin disrupts the double-layer membrane barrier, leading to proton motive force (PMF) dysregulation, reduced intracellular ATP levels, and impaired efflux pump activity. Collectively, this study highlights the potential of drug repurposing as an effective strategy to combat antimicrobial resistance and provides a foundation for the development of combination therapies against multidrug-resistant pathogens.