Modifying Antimicrobial Peptides with Albumin-Binding Molecules Enhances Membrane-Disrupting Efficacy by Modulating the Secondary Structure

Antimicrobial peptides (AMPs) are powerful tools in combating
drug-resistant
bacteria. However, their clinical application is hindered by poor
pharmacokinetics and suboptimal antimicrobial activity. This study
proposes a strategy to enhance the antimicrobial activity and biosafety
of AMPs by modification with albumin-binding molecules (ABMs). This
strategy was validated by employing two model peptides with moderate
antimicrobial efficacy. First, ABM modification stabilizes the secondary
structures, facilitating bacterial membrane disruption. Additionally,
modified AMPs target albumin in blood vessels, reducing renal clearance
in vivo. Moreover, this binding minimizes contact with blood and endothelial
cells, consequently diminishing vascular toxicity without compromising
antimicrobial activity. Molecular dynamic simulations followed by
experimental validation revealed new molecular insights into the mechanism
underlying AMP-mediated membrane disruption, confirming our design
strategy. This dual mechanism, structural stabilization and albumin-mediated
pharmacokinetic enhancement, addresses the key limitation of AMPs,
offering a versatile approach to develop potent, systemically safe
antimicrobial therapies.