Complexation-Aided Selectivity Amplification: A Strategy to Mitigate Peptidomimetics’ Toxicity Issues in Anti-Resistance Practices

Antimicrobial peptidomimetics (AMPMs) have valuable antiresistance features, but they generally suffer from insufficient killing selectivity for bacteria over eukaryotic cells, leading to limited therapeutic indices and inability to work with existing therapeutic strategies. Here, we report a strategy called complexation-aided selectivity amplification. By choosing an anionic polyelectrolyte that can form kinetically and thermodynamically stable complexes with an AMPM, the AMPM's selectivity for the more negatively charged prokaryotic cell membrane can be enhanced since a thermodynamically determined outcome, i.e., disruptive interaction with only prokaryotic but not eukaryotic cell membrane, can be assured. Thus, the AMPM-polyelectrolyte complex can be used as a low-toxicity alternative that allows safer use on cell or animal models and works with existing therapeutic strategies. Notably, the complex retains the key advantages of AMPMs, such as being resistance-resistant, broad-spectrum, and fast-killing. The broad applicability of this strategy is demonstrated with additional complexing polymers, AMPM, and antibiotics.