Repurposing loratadine to reverse colistin resistance in Klebsiella pneumoniae through targeting lipid A modification
Xiaoying Wu, Zhanzhe Ge, Haojie Zhan, Mengxiang Zheng, Yiming Feng, Yajun Zhai, Li Yuan, Jianhua Liu, Yushan Pan, Gongzheng Hu, Xiaoyuan Ma, Dandan He
TL;DR
Loratadine, an antihistamine, can help restore the effectiveness of colistin against drug-resistant Klebsiella pneumoniae by altering bacterial membranes.
Contribution
Loratadine is shown to reverse colistin resistance in K. pneumoniae by targeting lipid A modification and membrane disruption.
Findings
Loratadine restores colistin's bactericidal activity against resistant K. pneumoniae in vitro and in vivo.
Loratadine disrupts membrane barriers and reduces ATP levels in resistant bacteria.
Loratadine downregulates the lipid A-modifying enzyme EptB.
Abstract
The emergence of multidrug-resistant Klebsiella pneumoniae 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 K. pneumoniae. Our results demonstrate that loratadine significantly restores the bactericidal activity of colistin against colistin-resistant K. pneumoniae both in vitro and in vivo, 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…
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Taxonomy
TopicsAntibiotic Resistance in Bacteria · Immune Response and Inflammation · Antimicrobial agents and applications