Speaker
Description
The escalating threat of multidrug-resistant Gram-negative pathogens is compounded by their dual-membrane defenses, which severely limit the efficacy of conventional antibiotics. Antimicrobial peptides (AMPs) provide a promising alternative, yet their application is restricted by cytotoxicity and rapid proteolytic degradation.
Manudysins, rationally engineered derivatives of the human thrombin-derived peptide FRL16, were designed through stereochemical modification of protease-sensitive residues. This approach generated peptides that are protease-resistant, non-cytotoxic, and strongly membrane-disruptive. Atomistic molecular dynamics simulations demonstrated that Manudysins not only bypass the lipopolysaccharide-rich outer membrane, penetrating and destabilizing it, but also insert deeply into the phospholipid-rich inner membrane, adopting tilted conformations that drive severe bilayer perturbation.
These findings establish Manudysins as stable, membrane-active agents capable of overcoming both barriers of Gram-negative bacteria. By combining rational stereochemical design with molecular dynamics simulations, this study provides a blueprint for the development of next-generation antimicrobial peptides to address the post-antibiotic era.