Acid-Activated Antimicrobial Random Copolymers: A Mechanism-Guided Design of Antimicrobial Peptide Mimics

How to reduce the off-target adverse effects during antimicrobial administration remains an ongoing challenge. We show a mechanism-guided design of acid-activated antimicrobial peptide mimics (aSMAMPs) that have antibacterial activity triggered by acidic pH, a factor associated with many infected conditions. The cationicity of membrane-active antimicrobials is known to facilitate activity. By reinforcing a membrane-active antimicrobial random copolymer with an extra pH-responsive monomer, we obtain aSMAMP that is net neutral at physiological pH but net cationic at acidic pH. Plate killing assays indicate that Escherichia coli cells at pH 5.0 rather than those at pH 7.4 are susceptible to such aSMAMPs, whereas the opposite is true when challenged with conventional metabolic antibiotics. Comparison between the aSMAMPs and one homologue that is cationic at both pH conditions suggests that the acid-triggered antibacterial activity of aSMAMPs may be attributed to their pH-tunable net cationicity. At normal blood pH, these aSMAMPs demonstrate greatly diminished hemolytic toxicity against human erythrocytes. Taken together, such aSMAMPs show that switching on-or-off the cationic motif of a membrane-active antimicrobial via pH offers a feasible approach toward “smart” antimicrobials with activity triggered by acidic pH associated with many infected conditions, which may have implications in reducing the off-target adverse effects on both microbiota and host cells during antimicrobial administration.