Quaternized 1,2,3-Triazolyl Content and Modulation Potentiate Antibacterial and Antifungal Activities of Amphipathic Peptoids

Bioinspired from cationic antimicrobial peptides, sequence-defined triazolium-grafted peptoid oligomers (6- to 12-mer) were designed to adopt an amphipathic helical polyproline I-type structure. Their evaluation on a panel of bacterial strains (Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Enterococcus faecalis), pathogenic fungi (Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus), and human cells (hRBC, BEAS-2B, Caco-2, HaCaT, and HepG2) enabled the identification of two heptamers with improved activity to selectively fight Staphylococcus aureus pathogens. Modulation of parameters such as the nature of the triazolium and hydrophobic/lipophilic side chains, the charge content, and the sequence length drastically potentiates activity and selectivity. Besides, the ability to block the proinflammatory effect induced by lipopolysaccharide or lipoteichoic acid was also explored. Finally, biophysical studies by circular dichroism and fluorescence spectroscopies strongly supported that the bactericidal effect of these triazolium-grafted oligomers was primarily due to the selective disruption of the bacterial membrane.