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Simeprevir restores the anti-Staphylococcus activity of polymyxins

Yuan Wu1, Pingyun Wu1, Ruolan Wu1

  • 1Department of Laboratory Medicine, The Third Xiangya Hospital of Central South University, Changsha, Hunan, 410013, China.

AMB Express
|November 2, 2023
PubMed

Insights

Simeprevir combined with polymyxins shows synergistic antibacterial effects against methicillin-resistant Staphylococcus aureus (MRSA). This combination therapy is promising for treating MRSA infections with reduced toxicity.

Area of Science:

  • Microbiology
  • Infectious Diseases
  • Pharmacology

Background:

  • Methicillin-resistant Staphylococcus aureus (MRSA) presents a significant global health challenge due to its high mortality.
  • Polymyxins are primarily used for Gram-negative infections and have limited activity against S. aureus.
  • Combining antibiotics with adjuvants offers a strategy to combat difficult-to-treat infections and reduce toxicity.

Purpose of the Study:

  • To investigate the antibacterial activity of simeprevir (SIM) in combination with polymyxins against MRSA.
  • To evaluate the synergistic effects, cytotoxicity, and therapeutic potential of this combination.
  • To explore the mechanism of action, including membrane disruption.

Main Methods:

  • High-throughput screening and checkerboard assays were employed to assess synergistic antibacterial effects.
  • Time-growth curves, CCK-8 assays, and hemolysis assays evaluated antibacterial activity and cytotoxicity.
  • Biofilm inhibition assays, persister cell killing assays, and a murine subcutaneous abscess model were used for further evaluation.
  • Membrane integrity was assessed using SYTOX Green and DISC3(5) probes.

Main Results:

  • A synergistic antibacterial effect of SIM with polymyxins against S. aureus was confirmed in vitro.
  • The combination demonstrated efficacy in eradicating biofilms and killing persister cells.
  • In vivo studies in a murine model showed therapeutic potential with acceptable toxicity.
  • SIM was found to enhance the membrane-disrupting activity of polymyxins against MRSA.

Conclusions:

  • Simeprevir in combination with polymyxins, particularly polymyxin E (PE), exhibits promising therapeutic potential against MRSA infections.
  • This combination strategy may offer a viable treatment option for challenging MRSA infections.
  • The findings highlight a potential new approach to combatting antibiotic-resistant bacteria.
Keywords:
AntimicrobialDrug repurposingPersister cellsPolymyxinsSimeprevirStaphylococcus aureus

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