Targeted Design of Novel Antimicrobial Peptides against Staphylococcal Membranes

Abstract

Due to the rising worldwide concern of antibiotic resistance, the creation of new antimicrobial agents has become an essential necessity. Novel antimicrobial peptides (AMPs), celebrated for their extensive efficacy and minimal likelihood of resistance development, are considered among the most promising treatment options. This paper introduced the rational design and synthesis of a new antimicrobial peptide, RK7 (RKKYWLL), which targeted the biophysical differences between human and staphylococcal cell membranes to achieve selective disturbance and damage of the membrane. Models of human and staphylococcal cell membranes were first developed, subsequently followed by molecular docking screens to discover peptides with a strong affinity for staphylococcal membranes while demonstrating inertness toward human membranes. Molecular dynamics (MD) simulations showed that RK7 could specifically interact with the bacterial membrane. AI-assisted design suggested that RK7 is nontoxic and has good stability. Following antibacterial and cytotoxicity testing, RK7 was shown to be nontoxic to normal human cells while exhibiting significant staphylococcal inhibition. RK7 demonstrated a 98.14% inhibition rate against Staphylococcus at a dose of 62.5 μg/mL. This research provides a novel strategy for designing antimicrobial peptides based on compositional differences in cell membranes, offering an innovative approach for the targeted design of future antimicrobial agents.