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Abstract Antimicrobial resistance is a global healthcare challenge that urgently needs the development of new therapeutic agents. Antimicrobial peptides and mimics thereof are promising candidates but mostly suffer from inherent toxicity issues due to the non‐selective binding of cationic groups with mammalian cells. To overcome this toxicity issue, this work herein reports the synthesis of a smart antimicrobial dendron with masked cationic groups ( Gal‐Dendron ) that could be uncaged in the presence of β‐galactosidase enzyme to form the activated Enz‐Dendron and confer antimicrobial activity. Enz‐Dendron show bacteriostatic activity toward Gram‐negative ( P. aeruginosa and E. coli ) and Gram‐positive ( S. aureus ) bacteria with minimum inhibitory concentration values of 96 µ m and exerted its antimicrobial mechanism via a membrane disruption pathway, as indicated by inner and outer membrane permeabilization assays. Crucially, toxicity studies confirmed that the masked prodrug Gal‐Dendron exhibited low hemolysis and is at least 2.4 times less toxic than the uncaged cationic Enz‐Dendron , thus demonstrating the advantage of masking the cationic groups with responsive immolative linkers to overcome toxicity and selectivity issues. Overall, this study highlights the potential of designing new membrane‐disruptive antimicrobial agents that are more biocompatible via the amine uncaging strategy.
Shao et al. (Wed,) studied this question.