Modified horseshoe crab peptides target and kill bacteria inside host cells

Area of Science:

• Microbiology
• Immunology
• Biochemistry

Background:

• Intracellular bacteria, including uropathogenic Escherichia coli (UPEC), evade host defenses, complicating treatment.
• UPEC's ability to survive intracellularly necessitates novel therapeutic strategies beyond conventional antibiotics.

Purpose of the Study:

• To investigate cell-penetrating antimicrobial peptides as potential agents against intracellular UPEC.
• To evaluate the efficacy and safety of horseshoe crab-derived peptides, tachyplesin I and polyphemusin I, and their analogs.

Main Methods:

• Screening of antimicrobial peptides for activity against planktonic bacteria.
• Assessing peptide toxicity to mammalian cells.
• Evaluating the reduction of intramacrophage UPEC survival in vitro.
• Investigating peptide-antibacterial mechanisms using bacterial and membrane models.

Main Results:

• Tachyplesin I and polyphemusin I exhibited broad-spectrum antimicrobial activity.
• [I11A]tachyplesin I and [I11S]tachyplesin I analogs showed reduced mammalian cell toxicity while retaining antibacterial efficacy.
• These optimized peptides significantly reduced intracellular UPEC survival in an in vitro model.
• Peptides disrupted bacterial cell membranes, and sublethal concentrations enhanced UPEC susceptibility to zinc and innate macrophage defenses.

Conclusions:

• Cell-penetrating antimicrobial peptides are effective against intracellular UPEC, offering an alternative to conventional antibiotics.
• Optimized peptide analogs provide an improved therapeutic window for treating UPEC infections.
• These peptides target bacterial membranes and potentiate host innate immunity, highlighting their multifaceted therapeutic potential.