Molecular-Level Strategy from Bottom-Up to Acquire High-Efficiency Antimicrobial Peptides

The escalating threat of multidrug-resistant pathogens necessitates efficient antimicrobial development, in which antimicrobial peptides (AMPs) have been extensively studied due to their broad-spectrum antibiotic activity. Combining sum frequency generation and molecular dynamics simulation, we rationally designed AMPs by identifying two structural principles. Simply increasing the number of basic amino acids does not reliably improve antimicrobial efficacy; terminal (N’ and C’) phenylalanine residues can enhance AMP’s membrane interfacial activity via the hydrophobic effect. After two rounds of sequence optimization, among the derivatives we designed, an artificial AMP named GF demonstrated superior membrane binding (especially insertion) and spatial conformation stability. In vitro and in vivo evaluations revealed GF’s potential broad-spectrum efficacy against common bacteria and drug-resistant bacteria. Notably, GF exhibited enhanced antimicrobial potency over conventional antibiotics at lower concentrations. Our study established a bottom-up (mechanism-driven) design framework and provided a template for developing precision antimicrobials against resistant infections.