Short Synthetic <i>β</i>‐Sheet Forming Peptide Amphiphiles as Broad Spectrum Antimicrobials with Antibiofilm and Endotoxin Neutralizing Capabilities

Abstract

Abstract Although naturally occurring membrane lytic antimicrobial peptides (AMPs) and their analogs hold enormous promise for antibiotics‐resistant infectious disease therapies, significant challenges such as systemic toxicities, long peptide sequences, poor understanding of structure‐activity relationships, and the potential for compromising innate host defense immunity have greatly limited their clinical applicability. To improve the clinical potential of AMPs, a facile approach is adopted to design a series of short synthetic β ‐sheet folding peptide amphiphiles comprised of short recurring (X 1 Y 1 X 2 Y 2 ) n ‐NH 2 sequences, where X 1 and X 2 : hydrophobic residues (Val, Ile, Phe or Trp), Y 1 and Y 2 : cationic residues (Arg or Lys), and n: number of repeat units; with systematic variations to the cationic and hydrophobic residues to obtain optimized AMP sequences bearing minimal resemblance to naturally occurring sequences. The designed β ‐sheet forming peptides exhibit broad spectrum antimicrobial activities against various clinically relevant microorganisms, including Gram‐positive Staphylococcus epidermidis and Staphylococcus aureus , Gram‐negative Escherichia coli and Pseudomonas aeruginosa , and yeast Candida albicans , with excellent selectivities for microbial membranes. Optimal synthetic peptides with n = 2 and n = 3 repeat units, i.e., (IRIK) 2 ‐NH 2 and (IRVK) 3 ‐NH 2 , efficiently inhibit sessile biofilm bacteria growth leading to biomass reduction. Additionally, sequences with n = 3 repeat units effectively neutralize endotoxins while causing minimal cytotoxicities. Taken together, these findings clearly demonstrate that the rationally designed synthetic β ‐sheet folding peptides are highly selective, non‐cytotoxic at antimicrobial levels and have tremendous potential for use as broad spectrum antimicrobial agents to overcome multidrug resistance in a wide range of localized, systemic, or external therapeutic applications.