Enhancing the Antimicrobial Potency of Self-Assembling Antibiotics by Co-Assembly-Based Aggregation Modulation

The activity of many antimicrobial peptides (AMPs), a promising alternative to classical antibiotics, depends strongly on their aggregation-propensity and weak peptide association favor antimicrobial function, whereas stable assembly can reduce activity. Thus, modulation of intermolecular interactions offers a feasible way to enhance the potency of existing AMPs. However, a general strategy to achieve this objective has not been established. Here, we demonstrate that the spectrum of activity of Gram-positive-specific self-assembling AMP Fmoc-phenylalanine can be broadened by co-assembly with non-antibiotic Fmoc-glutamic acid. Biophysical assays confirmed that the co-assembled system disrupted bacterial membrane integrity, leading to cell death. The enhanced potency correlated with the reduced mechanical rigidity of the co-assembled hydrogel, as determined by rheological measurements, and molecular dynamics simulations further revealed that heterogeneous non-covalent interactions were detrimental to the fibril stability. These findings suggest that rationally designed co-assembling partners that weaken stabilizing non-covalent interactions can serve as a common strategy to enhance the antibacterial efficacy of existing AMPs.