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Antimicrobial peptide-induced inner membrane hyperpolarization is associated with antibiotic sensitization and

Jih-Chao Yeh1, Prakash Kishore Hazam1,2, You-Ying Lin1

  • 1Marine Research Station, Institute of Cellular and Organismic Biology, Academia Sinica, Jiaushi, Ilan, Taiwan, ROC.

Npj Antimicrobials and Resistance
|April 30, 2026
PubMed

Insights

The cationic peptide TP2-5 acts as an antibiotic adjuvant, enhancing susceptibility to drugs and reducing resistance in multidrug-resistant sepsis. It also modulates inflammation, improving survival in a sepsis model.

Area of Science:

  • Infectious Diseases
  • Microbiology
  • Immunology
  • Pharmacology

Background:

  • Antimicrobial resistance and dysregulated inflammation are key drivers of mortality in multidrug-resistant (MDR) sepsis.
  • Novel therapeutic strategies are urgently needed to combat MDR sepsis, including approaches that enhance existing antibiotic efficacy and modulate host inflammatory responses.

Purpose of the Study:

  • To evaluate the cationic peptide TP2-5 as a low-dose antibiotic adjuvant for treating MDR sepsis.
  • To investigate the mechanisms by which TP2-5 enhances antibiotic susceptibility and modulates host inflammatory responses.

Main Methods:

  • Evaluated TP2-5's effect on antibiotic susceptibility of MDR *E. coli* in broth and human serum.
  • Assessed MIC escalation during serial passage in the presence of TP2-5 and antibiotics.
  • Utilized membrane potential assays and cryo-electron tomography to study TP2-5's interaction with bacterial envelopes.
  • Investigated TP2-5's effect on lipopolysaccharide (LPS) neutralization and Toll-like receptor 4 (TLR4)-dependent cytokine production.
  • Tested TP2-5's efficacy in a murine polymicrobial cecal ligation and puncture (CLP) sepsis model.

Main Results:

  • TP2-5, at sub-inhibitory concentrations, enhanced antibiotic susceptibility of MDR *E. coli* and attenuated MIC escalation during serial passage.
  • TP2-5 induced bacterial envelope perturbation, characterized by inner-membrane hyperpolarization, with preferential interaction with LPS and anionic phospholipids.
  • TP2-5 neutralized LPS and reduced TLR4-dependent cytokine production.
  • In the CLP sepsis model, TP2-5 alone or with meropenem resulted in 100% survival, reduced bacterial burden, and decreased systemic inflammatory cytokines.

Conclusions:

  • The cationic peptide TP2-5 exhibits a multifunctional adjuvant profile, demonstrating both antibacterial enhancement and host-directed immunomodulatory effects.
  • TP2-5 supports combined antibacterial and anti-inflammatory actions, offering a promising strategy for treating MDR sepsis.
  • Further research is needed to elucidate the in vivo role of hyperpolarization in TP2-5's protective effects and its impact on attenuated MIC escalation.

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