Antibiotic-like properties of cationic linear-dendritic macromolecules having guanidinium peripheral groups

The urgent development of alternatives to conventional antibiotics is essential to address the escalating burden of bacterial antibiotic resistance. Therefore, in this work, we focus on amphiphilic antimicrobial agents having a linear-dendritic structure. They are derived from the first four generations of dendritic polyesters derived from 2,2-bis(hydroxymethyl)propionic acid that are linked to different hydrophobic alkyl chains at the focal point and decorated with cationic guanidinium groups at their periphery. The preparation of these compounds is accomplished through a versatile and orthogonal click chemistry-based strategy. Firstly, alkyl chains are introduced at the focal point of the dendrons via a Cu(I)-catalyzed azide-alkyne cycloaddition. Subsequently, Boc-protected guanidinium groups are attached to the dendron periphery using a thiol-ene reaction, followed by deprotection to yield the cationic guanidinium groups. These amphiphilic linear-dendritic compounds exhibit antimicrobial activity against Gram-positive ( Staphylococcus aureus ATCC 25923) and Gram-negative ( Escherichia coli S17) bacteria. The antimicrobial activity and cytotoxicity toward eukaryotic cells, specifically, human dermal fibroblast, HaCaT human keratinocytes and J774A.1 mouse monocyte-macrophages, can be finely optimized to obtain antibiotic-like materials by varying the dendritic generation and adjusting the hydrophobic/hydrophilic balance, which is mainly governed by the length of the alkyl chain at the focal point of the dendron. The orthogonal click chemistry strategy enables facile modulation of the hydrophobic/hydrophilic balance from a common dendritic scaffold, achieving a linear-dendron agent that displays antimicrobial activity comparable to that of conventional antibiotics, while maintaining high cytocompatibility. • Guanidium-dendritic polyesters exhibit antimicrobial activity against bacteria. • Antimicrobial and cytotoxic effects depend on hydrophobicity and dendron generation. • Linear-dendritic macromolecules act by disrupting bacterial membranes.