Structure‐Activity Relationship Study to Develop Peptide Amphiphiles as Species‐Specific Antimicrobials

Abstract

Antimicrobial peptide amphiphiles (PAs) are a promising class of molecules that can disrupt the bacterial membrane or act as drug nanocarriers. In this study, we prepared 33 PAs to establish supramolecular structure‐activity relationships. We studied the morphology and activity of the nanostructures against different Gram‐positive and Gram‐negative bacterial strains (such as Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Acinetobacter baumannii). Next, we used principal component analysis (PCA) to determine the key contributors to activity. We found that for S. aureus, the zeta potential was the major contributor to the activity while Gram‐negative bacteria were more influenced by the partition coefficient (LogP) with the following order P. aeruginosa > E. coli > A. baumannii. We also performed a study of the mechanism of action of selected PAs on the bacterial membrane assessing the membrane permeability and depolarization, changes in zeta potential and overall integrity. We studied the toxicity of the nanostructures against mammalian cells. Finally, we performed an in vivo study using the wax moth larvae to determine the therapeutic efficacy of the active PAs. This study shows cationic PA nanostructures can be an intriguing platform for the development of nanoantibacterials.

Enhanced Hydrogen Bonding by Urea Functionalization Tunes the Stability and Biological Properties of Peptide Amphiphiles

“…Therefore, we believe the antimicrobial efficacy of cationic PAs strongly correlates with their ability to attach and disrupt the bacterial membrane. This process is influenced by the interplay between the cationic surface charge, the hydrophobicity, and the internal cohesion of the PA assemblies. , We tested the antimicrobial activity of the cationic PAs against Staphylococcus aureus JE2 (a Gram-positive organism) and Acinetobacter baumannii (a Gram-negative organism) to study whether the urea modification could affect the PA–bacterial membrane interaction. The MIC and MBC are shown in Figure A.…”