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A Potential Nontraditional Approach To Combat

Xiaoming Wang1,2, Ting Liu1, Xi Lv1

  • 1MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China.

Antimicrobial Agents and Chemotherapy
|June 8, 2023
PubMed
Summary
This summary is machine-generated.

Melatonin boosts tigecycline effectiveness against drug-resistant Klebsiella pneumoniae by disrupting efflux pumps. This combination therapy shows promise for treating infections caused by bacteria carrying the TMexCD1-TOprJ1 gene.

Keywords:
melatonin/tigecycline combinationmelatonin/tigecycline hybridsynergistic effecttigecycline resistance

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Area of Science:

  • Microbiology
  • Pharmacology
  • Infectious Diseases

Background:

  • The emergence of transferable resistance-nodulation-division (RND)-type efflux pumps, such as TMexCD1-TOprJ1, poses a significant global health threat, conferring resistance to critical antibiotics like tigecycline.
  • Klebsiella pneumoniae strains harboring the TMexCD1-TOprJ1 efflux pump exhibit reduced susceptibility to tigecycline, complicating treatment options for infections.

Purpose of the Study:

  • To investigate the potential synergistic effect of melatonin in combination with tigecycline against Klebsiella pneumoniae strains carrying the TMexCD1-TOprJ1 efflux pump.
  • To elucidate the underlying mechanisms by which melatonin enhances tigecycline's antibacterial activity.

Main Methods:

  • In vitro susceptibility testing to evaluate the synergistic antibacterial activity of melatonin and tigecycline.
  • Assessment of tigecycline accumulation within bacterial cells.
  • Analysis of bacterial cell membrane integrity and cell content leakage.
  • In vivo validation using a murine thigh infection model.

Main Results:

  • Melatonin demonstrated a synergistic effect, significantly enhancing the antibacterial efficacy of tigecycline against TMexCD1-TOprJ1-positive Klebsiella pneumoniae.
  • The combination disrupted the proton driving force and efflux pump function, leading to increased intracellular accumulation of tigecycline.
  • Damage to bacterial cell membrane integrity and subsequent leakage of cellular contents were observed.
  • The synergistic effect was confirmed in a murine thigh infection model, showing improved treatment outcomes.

Conclusions:

  • Melatonin acts synergistically with tigecycline to overcome TMexCD1-TOprJ1-mediated resistance in Klebsiella pneumoniae.
  • The combination therapy enhances tigecycline efficacy by increasing drug accumulation and compromising bacterial cell integrity.
  • The melatonin/tigecycline combination represents a promising therapeutic strategy for combating infections caused by multidrug-resistant bacteria carrying the TMexCD1-TOprJ1 gene.