The global public health threat of antimicrobial resistance has led the scientific community to highly engage into research on alternative strategies to the traditional small molecule therapeutics. Here, we review one of the most popular alternatives amongst basic and applied research scientists, synthetic antimicrobial peptides. The ease of peptide chemical synthesis combined with emerging engineering principles and potent broad-spectrum activity, including against multidrug-resistant strains, has motivated intense scientific focus on these compounds for the past decade. This global effort has resulted in significant advances in our understanding of peptide antimicrobial activity at the molecular scale. Recent evidence of molecular targets other than the microbial lipid membrane, and efforts towards consensus antimicrobial peptide motifs, have supported the rise of molecular engineering approaches and design tools, including machine learning. Beyond molecular concepts, supramolecular chemistry has been lately added to the debate; and helped unravel the impact of peptide self-assembly on activity, including on biofilms and secondary targets, while providing new directions in pharmaceutical formulation through taking advantage of peptide selfassembled nanostructures. We argue that these basic research advances constitute a solid basis for promising industry translation of rationally designed synthetic peptide antimicrobials, not only as novel drugs against multidrug-resistant strains but also as components of emerging antimicrobial biomaterials. This perspective is supported by recent developments of innovative peptidebased and peptide-carrier nanobiomaterials that we also review.

Peptides can serve as versatile therapeutics with a highly modular structure and tunable biophysical properties. In particular, the efficacy of peptide antibiotics against drug-resistant pathogens is of great promise, as few new classes of antibiotics are being developed to overcome the ever-increasing bacterial resistance to contemporary drugs. This work reports biophysical and antimicrobial studies of a designed library of ultrashort peptides that self-assemble into hydrogels at concentrations as low as 0.5% w/v in buffered saline, as confirmed by rheology. The hydrogels are constituted by β-sheet-rich nanofibril networks, as determined by biophysical techniques including spectroscopy (attenuated total reflectance Fourier transform infrared spectroscopy and Congo red binding assay), short-and wide-angle X-ray scattering, and electron microscopy. Both peptide solutions and self-assembled hydrogels show potent antimicrobial activity against S. aureus and Pseudomonas aeruginosa by membrane lysis. These peptides also displayed selectivity toward bacterial cells over human dermal fibroblasts in vitro, as determined from Live/Dead, scanning electron microscopy, and coculture assays. This work reports an antimicrobial self-assembling motif of only three residues comprising an aromatically acylated cationic D-Dab/Lys amino acid, a second cationic residue, and naphthylalanine that heavily influences the self-assembly of these peptides into hydrogels. The variations in the antimicrobial activity and self-assembly properties between analogues may have implications in future studies on the correlation between self-assembly and biological activity in ultrashort peptides.

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The para-fluoro-thiol reaction (PFTR) is a modern name for the much older concept of a nucleophilic aromatic substitution reaction in which the para-position fluorine of a perfluorinated benzene moiety is substituted by a thiol. As a rapid and mild reaction, the PFTR is a useful technique for the post-synthetic modification of macromolecules like peptides on the solid phase. This reaction is of great potential since it allows for peptide chemists to access the vast catalogue of commercially available thiols with diverse structures to conjugate to peptides, which may impart favorable biological activity, particularly in antimicrobial sequences. This work covers the generation of a library of antimicrobial peptides by modifying a relatively inactive tetrapeptide with thiols of various structures using the PFTR to grant antimicrobial potency to the core sequence. In general, nucleophilic substitution of the peptide scaffold by hydrophobic thiols like cyclohexanethiol and octanethiol imparted the greatest antimicrobial activity over that of hydrophilic thiols bearing carboxylic acid or sugar moieties, which were ineffectual at improving the antimicrobial activity. The general trend here follows expected structure−activity relationship outcomes like that of changing the acyl group of lipopeptide antibiotics and is encouraging for the use of this reaction for structural modifications of antimicrobial sequences further.