FTIR Spectroscopy Suggests a Revised Mode of Action for the Cationic Side-Chain Effect of Ionic Liquids

Over the past decades, ionic liquids (ILs) have gained considerable attention from the scientific community because of their versatile and designable properties. As a result, there are numerous IL applications, not only in organic synthesis, catalysis, or extraction but also as active pharmaceutical ingredients or novel antimicrobials. While considerable effort has been put into developing quantitative structure-activity relationship (QSAR) models for IL toxicity prediction, little is known about their actual mode of action. In this study, Fourier transform infrared (FTIR) spectroscopy is used to monitor IL induced molecular responses directly at the cellular level. Investigation of the well-known cationic alkyl side-chain effect (increasing side-chain length leads to increasing toxicity) of imidazolium- and ammonium-based ILs on two bacterial pathogens, enteropathogenic  Escherichia coli (EPEC) and methicillin-resistant Staphylococcus aureus (MRSA), surprisingly revealed two distinct modes of action. Contrary to prior models, it was only for [TMC₁₆A][Cl], where a molecular response in the membrane was found, while ILs with shorter side-chain lengths predominantly affected bacterial proteins. The results of this study highlight the importance of further direct investigations of the impact of ILs at the cellular level to improve toxicity prediction and assess the usefulness of spectroscopic methods, such as FTIR spectroscopy at achieving this goal.