Engineered α‐Helical Peptides with Chelating Agents as Approach to Antibacterial Therapeutics

This study introduces a new class of α-helical antimicrobial peptides designed to combat multidrug-resistant bacteria. The peptides were created using a structure-based approach guided by the main mechanical forces (MMFs) methodology, which promotes stable helical conformations by considering chemical interactions between amino acid side chains. Key features of the design of these peptides include: (1) amphipathic nature: hydrophobic and cationic residues are strategically positioned on opposite sides of the helix to disrupt bacterial membranes and (2) MMFs approach: enables precise control over the peptide's 3D structure through dihedral angle calculation. The peptides exhibited antimicrobial activity against various bacterial strains, including both Gram-positive and Gram-negative species, as well as a multidrug-resistant pathogen. This effect was particularly enhanced when coadministered with allomaltol, a chelating agent capable of sequestering essential metals (such as iron), thereby disrupting bacterial metabolism and providing a secondary mechanism of action. This work validates the MMFs methodology as an accurate prediction tool for peptide secondary structure, reproducing NMR-derived helical features of the HT2 peptide and enabling rational design of new analogs. Moreover, the covalent introduction of a chelating group markedly improved antimicrobial potency (MIC 18.75 μM vs. 300 μM), confirming the functional synergy between amphipathic helicity and metal-ion sequestration.