Structure-Function Regulation of Proteolytically Stable Amphiphilic Peptide-Based Soft Materials With Antimicrobial Efficacy Against Drug-Resistant Strains and Anticancer Activity in Triple-Negative Breast Cancer Cells.

The rapid progress of multidrug-resistant (MDR) bacterial infections and the clinical aggressiveness of triple-negative breast cancer (TNBC) possess a great problem to human beings. It necessitates the discovery and development of multifunctional therapeutic biomaterials. Herein, we report two enzymatically stable short cationic peptide hydrogelators comprising of N-terminal lysine headgroups, non-coded amino acid spacers, aromatic phenylalanine residues, and dodecylamine tails. These amphiphilic peptides are rapidly self-assembled in Tris-HCl buffer (pH 7.4) to form hydrogels with nanofibrillar network. Remarkably, both of these hydrogelators exhibit potent antibacterial activity against several Gram-positive and Gram-negative drug-resistant strains, functioning through multitiered mechanism including membrane permeabilization, trans-membrane depolarization, and intracellular reactive oxygen species (ROS) generation. Moreover, one of these peptide amphiphiles demonstrates a significant anticancer efficacy (with IC50 value of 6.9 µM) against human TNBC cells by activating the extrinsic caspase-8/caspase-3-driven apoptotic pathway and reversing epithelial-to-mesenchymal transition (EMT). Interestingly, the peptide with centrally located amino acid residue with lesser number of methylene units than that of the other peptide shows better anticancer efficacy and less antimicrobial activity. This study vividly demonstrates a tunable class of proteolytically stable amphiphilic peptide gelators with potential antimicrobial as well as anticancer activities establishing a structure-function relationship of these bioactive peptide scaffolds suggesting a versatile blueprint for peptide-based next-generation soft bioactive materials.