Bacterial Phospholipid-Inducible Helix-Transformable Antimicrobial Polypeptides.

Area of Science:

• Biochemistry
• Molecular Biology
• Antimicrobial Research

Background:

• Antimicrobial peptides (AMPs) are crucial for innate immunity but often exhibit cytotoxicity.
• The helical structure of AMPs enhances bactericidal effects but also mammalian cell penetration.
• Developing AMPs with improved selectivity is essential for therapeutic applications.

Purpose of the Study:

• To design and characterize a bacterial phospholipid-inducible, helix-transformable antimicrobial polypeptide (HT-AMP) for enhanced antimicrobial selectivity.
• To investigate the structure-activity relationship of the HT-AMP, C6-10, in response to bacterial phospholipids.
• To evaluate the in vivo efficacy and safety of the developed HT-AMP.

Main Methods:

• Design of C6-10, an HT-AMP with a specific charge-to-backbone span.
• Assessment of intrinsic helicity and conformational changes upon interaction with bacterial phospholipids (phosphatidylglycerol).
• Evaluation of mammalian cell penetration, mitochondrial damage, and in vivo antibacterial activity in infection models.

Main Results:

• C6-10 exhibits moderate intrinsic helicity, reducing mammalian cell penetration and mitochondrial damage.
• Upon binding to bacterial phosphatidylglycerol, C6-10's helicity increases significantly, enhancing antibacterial activity.
• C6-10 demonstrated low organ toxicity and significant efficacy in bladder infection and sepsis models.

Conclusions:

• The bacterial phospholipid-triggered helix-transformable strategy effectively improves antimicrobial selectivity.
• HT-AMPs represent a promising class of therapeutics with reduced host cell toxicity.
• This approach offers a new avenue for developing safer and more effective antimicrobial agents.