Membrane-Active Peptides Derived from Natural Transmembrane Domains Function as Antibiotic Potentiators

Area of Science:

• Microbiology
• Biochemistry
• Drug Discovery

Background:

• Antimicrobial resistance (AMR) is a global health crisis driven by bacterial resistance mechanisms.
• Traditional antibiotics face challenges due to evolved bacterial defenses.
• Novel therapeutic strategies are urgently needed to overcome AMR.

Purpose of the Study:

• To investigate if peptides from transmembrane (TM) segments of membrane proteins can permeabilize bacterial membranes.
• To determine if such peptides can potentiate the activity of existing antibiotics against resistant bacteria.
• To explore the potential of these peptides as novel antibacterial agents.

Main Methods:

• Peptides were designed based on the AcrB TM8 sequence from the AcrAB-TolC efflux protein.
• Experiments were conducted using *Escherichia coli* ( *E. coli*).
• Assays included *in vitro* liposome-based studies and *in vivo* fluorescence-based methods to assess membrane permeabilization and antibiotic potentiation.

Main Results:

• AcrB TM8 peptides, including a scrambled analog, resensitized *E. coli* to cloxacillin and nalidixic acid.
• Peptide treatment resulted in a 50-100% reduction in bacterial growth compared to single treatments.
• Studies confirmed peptide-induced permeabilization of bacterial outer and inner membranes.

Conclusions:

• Membrane proteins contain peptide sequences with potent membrane-active properties.
• These peptides can enhance antibiotic efficacy, offering a strategy against Gram-negative bacterial infections.
• The findings provide a basis for designing synergistic membrane-active peptides for combating AMR.