Synthetic Anionophores Enhance the Activity of Anionic Drugs.

Lipid bilayers pose a major barrier to the passive diffusion of anionic species, including many carboxylate-containing drugs. This limited membrane permeability can reduce drug efficacy and allow bacteria to deploy various defense mechanisms. In this study, we show that small synthetic anionophores can significantly enhance the antibacterial activity of anionic antibiotics by accelerating their transmembrane transport. In liposomes, these anionophores increase the transmembrane transport rate of carboxylate drugs by over two orders of magnitude, even when present in catalytic amounts. In bacteria, the same artificial carriers amplify the activity of clinically used anionic antibiotics, markedly enhancing their antimicrobial activity against both Gram-positive and Gram-negative strains. Notably, the extent of this activity enhancement directly correlates with the carrier-induced increase in drug permeability. These results demonstrate that synthetic anion carriers can improve not only membrane permeability but also the therapeutic performance of anionic drugs, offering a promising strategy for overcoming permeability-related resistance in drug design.