Tailoring the Physicochemical Properties of Antimicrobial Peptides onto a Thiazole-Based γ-Peptide Foldamer

Abstract

Antimicrobial peptides (AMPs) are amphipathic molecules displaying broad-spectrum bactericidal activity, providing opportunities to develop a new generation of antibiotics. However, their use is limited either by poor metabolic stability or by high hemolytic activity. We herein addressed the potential of thiazole-based γ-peptide oligomers named ATCs as tunable scaffolds to design polycationic AMP mimetics. Knowing the side chain distribution along the backbone, we rationally designed facially amphiphilic sequences with bactericidal effect in the micromolar range. Since no hemolytic activity was detected up to 100 μM, this class of compounds has shown the potential for therapeutic development.

α,β‐Unsaturated γ‐Peptide Foldamers

“…However, the antimicrobial effects were not optimal and the activities toward Gram + strains were reinforced with the increase in peptide length (see Figure 8, compound 69). By contrast, the scrambled analog 70 was less active confirming that segregation of the [69] with permission from the American Chemical Society. cationic charges was crucial for the antimicrobial action.…”

“…[68] Considering the vinylogous γ-AAs, three families of non-natural antibacterials were reported: A gramicidin S (GS) analog incorporating ATC residues as β-turn mimics, and antimicrobial foldamers based on ATC and 1 : 1 α/E-dγAAs oligomers. [55,[69][70] Gramicidin S (GS) is a potent antibacterial cyclodecapeptide. [71] Importantly, its amphiphilic C 2 -symmetrical antiparallel β-sheet conformation is essential for its antimicrobial activity.…”

“…More recently, the ATC 9-helix was addressed as scaffold to design amphipathic antimicrobial foldamers. [69] Based on the side chain distribution along the helical axis, we rationally designed facially amphiphilic sequences of different lengths (from trimers to dodecamers) bearing from two to eight cationic charges on one face (Figure 8b). The two other faces were spanned with methyl or isopropyl substituents in order to modulate the hydrophobic balance, a crucial parameter influencing both selectivity and affinity for bacteria.…”

“…d) SEM micrographs of i/untreated E. coli on glass platelets and ii/after 60 min incubation with 8 × MIC of 70. Reproduced from reference[69] with permission from the American Chemical Society.…”

Helical Antimicrobial Peptide Foldamers Containing Non‐proteinogenic Amino Acids

“…[76] Maillard and co-workers developed unique foldamers composed of constrained heterocyclic γ-amino acids built around a thiazole ring, named 4-amino (methyl)-1,3-thiazole-5-carboxylic acid (ATC). [77] ATC oligomers form a C3-symmetry helix with three residues required to achieve a whole turn, like 3 10 -helices. Amphipathic ATC-based foldamers showed strong antimicrobial activity against Grampositive and Gram-negative bacteria without significant hemo-lytic activity.…”