Short Arg- and Trp-Rich Lipopeptides Kill Resistant Bacterial Pathogens via Effective Membrane Disruption

Antimicrobial peptides (AMPs) represent a promising alternative to conventional antibiotics due to their rapid bactericidal actions via membrane disruptions, making it difficult for pathogenic microbes to develop antimicrobial resistance (AMR). This work reported that lipopeptides rich in Arginine (R) and Tryptophan (W), namely, C₁₂RRWW, C₁₂WWRR, and C₁₂RWWR, where C₁₂ denotes a lauroyl chain, were antimicrobial against resistant and clinically isolated <i>Escherichia coli</i> and <i>Staphylococcus aureus</i> strains, with C₁₂RRWW achieving a high potency against <i>S. aureus</i> and <i>E. coli</i> and fast eradication of <i>Pseudomonas aeruginosa</i> compared to polymyxin B. Neutron reflection (NR) and small-angle neutron scattering (SANS) unravelled structural disruptions to the bacterial membranes that were well correlated to the antimicrobial actions observed from fluorescent and antimicrobial assays. This work demonstrates the power of NR and SANS at revealing the eradications of different pathogens via selective bacterial membrane targeting, crucial to the rational design of new AMPs for the control of AMR outbreak.