Melatonin overcomes MCR-mediated colistin resistance in Gram-negative pathogens

Yuan Liu, Yuqian Jia, Kangni Yang, Ziwen Tong, Jingru Shi, Ruichao Li, Xia Xiao, Wenkai Ren, Rüdiger Hardeland, Russel J. Reiter, Zhiqiang Wang, Zhiqiang Wang, Wenkai Ren, Yuan Liu

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Emergence, prevalence and widely spread of plasmid-mediated colistin resistance in Enterobacteriaceae strongly impairs the clinical efficacy of colistin against life-threatening bacterial infections. Combinations of antibiotics and FDA-approved non-antibiotic agents represent a promising means to address the widespread emergence of antibiotic-resistant pathogens. Methods: Herein, we investigated the synergistic activity between melatonin and antibiotics against MCR (mobilized colistin resistance)-positive Gram-negative pathogens through checkerboard assay and time-killing curve. Molecular mechanisms underlying its mode of action were elucidated. Finally, we assessed the in vivo efficacy of melatonin in combination with colistin against drug-resistant Gram-negative bacteria. Results: Melatonin, which has been approved for treating sleep disturbances and circadian disorders, substantially potentiates the activity of three antibiotics, particularly colistin, against MCR-expressing pathogens without enhancing its toxicity. This is evidence that the combination of colistin with melatonin enhances bacterial outer membrane permeability, promotes oxidative damage and inhibits the effect of efflux pumps. In three animal models infected by mcr-1-carrying E. coli, melatonin dramatically rescues colistin efficacy. Conclusion: Our findings revealed that melatonin serves as a promising colistin adjuvant against MCR-positive Gram-negative pathogens.

Original languageEnglish (US)
Pages (from-to)10697-10711
Number of pages15
JournalTheranostics
Volume10
Issue number23
DOIs
StatePublished - 2020

Keywords

  • Antibiotic adjuvant
  • Bacterial infections
  • Colistin
  • Gram-negative pathogen
  • Melatonin

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Pharmacology, Toxicology and Pharmaceutics (miscellaneous)

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